What is claimed is:
1. A process for preparing a compound of Formula I:
I or salt form thereof, wherein: R1 is H; R2 is Cj-Cg alkyl, -CH2-O-(d-C8 alkyl), C(0)O-(C C8 alkyl), -C(O)NH-(CrC8 alkyl), CrC4 haloalkyl, or CH2OH; R3 , R4, R5 , and R6 are each, independently, H, halo, Cι-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, CrC8 haloallcyl, hydroxy, mercapto, OR9, SR9, alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(0)NH-alkyl, hydroxyalkyl, NR10RU, CN, NO2, heterocycloallcyl, aryl, or heteroaryl, wherein said aryl and heteroaryl can be substituted with one or more substituents selected from Ci-Cg allcyl, halo, Ci-Cg haloallcyl, and alkoxy; or R4 and R5 together with the atoms to which they are attached form a 5- or 6- member heterocyclic ring having one O atom; R7a and R7b are each, independently, H, halo, Cι-C8 allcyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, CrC8 haloallcyl, alkoxyallcyl, hydroxy, C(0)-alkyl, C(O)O-allcyl, C(O)NH-alkyl, or hydroxyallcyl, or R a and R together with the carbon atom to which they are attached form a C3-C7 cycloallcyl group; R8a and R8b are each, independently, H, halo, Cι-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloallcyl, CrC8 haloalkyl, alkoxyallcyl, hydroxy, C(0)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyallcyl, or R8a and R8b together with the carbon atom to which they are attached form a C3-C7 cycloallcyl group; R9 is H, Cι-C8 alkyl, C C8 alkenyl, Cι-C8 alkynyl, C3-C7 cycloalkyl, Cι-C8 haloalkyl, aralkyl, aryl, heteroaryl, heteroarylallcyl, or allyl; R10 and R11 are each, independently, H, CrC8 allcyl, C C8 alkenyl, C]-C8 alkynyl, C3-C7 cycloalkyl, C C8 haloalkyl, arallcyl, aryl, heteroaryl, heteroarylallcyl, or allyl, or R10 and Rn together with the N atom to which they are attached form a heterocyclic ring; comprising reacting a compound of Formula II:
with a reducing agent optionally in the presence of a Lewis acid for a time and under conditions suitable for forming said compound of Formula I or salt form thereof.
2. The process of claim 1 wherein said reducing agent comprises a borane. I
3. The process of claim 1 wherein said reducing agent comprises BH3.
4. The process of claim 1 wherein said reducing agent comprises a metal hydride.
5. The process of claim 1 wherein said reducing agent comprises a borohydride or aluminum hydride.
6. The process of claim 1 wherein: R2 is C,-Cg alkyl, -CH2-O-(C,-C8 allcyl), C(O)O-(C C8 allcyl), -C(O)NH-(C C8 alkyl), OH, or
CH2OH R3 and R6 are each H; R4 and R5 are each, independently, H, halo, Cι-C8 haloallcyl, hydroxy, OR9, SR9, alkoxyalkyl, NHR10, NR10Rπ, aryl, or heteroaryl, wherein said aryl can be substituted with up to two substituents selected from C]-C8 alkyl, halo, Cι-C8 haloallcyl, and alkoxy, and said heteroaryl can be optionally substituted with up to two substituents selected from halogen and d-Cg alkyl; or R4 and R5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; R7a is H; R7b is H or Cι-C8 allcyl; R8a and R8b are each H; and R10 and R11 are each, independently, Ci-Cg alkyl, Cι-C8 alkenyl, Cι-C8 haloallcyl, aryl, heteroaryl, arallcyl, heteroarylallcyl, or allyl; provided that: (A) if R2 is methyl and R4 is H, then R5 is not thiazole, substituted thiazole or a thiazole derivative; and
(B) if R7a is H and R7b is other than H, then neither R4 nor R5 can be H.
7. The process of claim 6 wherein R2 is methyl, ethyl, n-propyl, or isopropyl.
8. The process of claim 6 wherein R2 is methyl.
9. The process of claim 6 wherein R4 is Cl, Br, haloallcyl, CF3, thiophenyl, furanyl, pyrrolyl, pyrazolyl, or imidazolyl.
10. The process of claim 6 wherein R4 is Cl.
11. The process of claim 6 wherein R5 is methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, or phenyl, wherein said imidazolyl is optionally substituted by one or more halo or methyl and said phenyl is optionally substituted with up to two substituents selected from d-C8 alkyl, C C8 haloalkyl, halo, and alkoxy.
12. The process of claim 6 wherein R5 is H. J
13. The process of claim 1 wherein: R2 is Cι-C4 alkyl, -CH2-0-(d-C4 alkyl), C C4 haloalkyl, or CH2OH; R3 , R4, R5 , and R6 are each, independently, H, halo, C C alkyl, C1-C4 haloallcyl, hydroxy, NH2, CN, or NO2; and R7a ^ R7bj R8a ^ ^ R8b & Q Q&Qk JJ. provided that: (TT) when R2 is CrC4 alkyl, -CH2-O-(d-C4 alkyl), or CH2OH, then R3 and R6 are not both H; and (I) when R2 is CH3, then R3, R4, and R6 are each H and R5 is not H or isopropyl.
14. The process of claim 13 wherein R2 is d-C4 allcyl or C1-C4 haloallcyl.
15. The process of claim 13 wherein R2 is methyl, ethyl, isopropyl, n-butyl, or CF3.
16. The process of claim 13 wherein R3, R4, R5, and R6 are each, independently, H, methyl, NH2, CN, halo, CF3, NO2, or OH.
17. The process of claim 1 wherein R7a, R7b, R8a, and R8b are each H.
18. The process of claim 1 wherein R3 and R6 are each H.
19. The process of claim 1 wherein R , R , and R are each H,
20. The process of claim 1 wherein R4 is halo.
21. The process of claim 1 wherein R is Cl.
22. The process of claim 1 wherein R is CrC alkyl
23. The process of claim 1 wherein R2 is methyl.
24. The process of claim 1 wherein R2 is CrC4 alkyl, R3 is H, R4 is halo, R5 is H, R6 is H, R7a is H, R7b is H, R8a is H, and R8b is H.
25. The process of claim 1 wherein R is Me, R is H, R4 is Cl, R5 is H, R5 is H, R7 7aa is H, R >77bb is H, R , 8a is H, and R* 8bD is H.
26. The process of claim 1 wherein said compound of Formula I has an S configuration at the carbon bearing R2.
27. The process of claim 1 wherein said compound of Formula I has an R configuration at the carbon bearing R2.
28. A process for preparing a compound of Formula II:
II or salt form thereof, wherein: R1 is H or d-C8 alkyl; R2 is d-Cg alkyl, -CH2-O-(C,-C8 alkyl), C(O)O-(C C8 allcyl), -C(O)NH-(d-C8 alkyl), OH, C,- C4 haloallcyl, or CH2OH;
R3 , R4, R5 , and R6 are each, independently, H, halo, Cι-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, d-C8 haloalkyl, hydroxy, mercapto, OR9, SR9, alkoxyalkyl, C(O)-alkyl, C(O)O-allcyl, C(O)NH-alkyl, hydroxyalkyl, NR10Rn, CN, NO2, heterocycloallcyl, aryl, or heteroaryl, wherein said aryl and heteroaryl can be substituted with one or more substituents selected from Ci-Cg alkyl, halo, C]-C8 haloallcyl, and alkoxy; or R4 and R5 together with the atoms to which they are attached form a 5- or 6- member heterocyclic ring having one O atom; R7a and R7b are each, independently, H, halo, CrC8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloallcyl, C C8 haloalkyl, alkoxyallcyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, or R7a and R7b together with the carbon atom to which they are attached form a C3-C7 cycloalkyl group; R8a and R8b are each, independently, H, halo, Cι-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloallcyl, Cι-C8 haloalkyl, alkoxyallcyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyallcyl, or R8a and R8b together with the carbon atom to which they are attached form a C3-C7 cycloallcyl group; R9 is H, Cι-C8 alkyl, C C8 alkenyl, d-Cg alkynyl, C3-C7 cycloalkyl, Ci-Cg haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl; R10 and Ru are each, independently, H, Ci-Cg alkyl, Ci-Cg alkenyl, Cι-C8 alkynyl, C3-C7 cycloallcyl, Cι-C8 haloalkyl, arallcyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R10 and R11 together with the N atom to which they are attached form a heterocyclic ring; comprising reacting a compound of Formula III:
III or salt form thereof, wherein: L is halo, hydroxy, C]-C8 alkoxy, Cι-C8 thioalkoxy, Cι-C8 acyloxy, -OSO2R, or
-OSi(R')3; R is Cι-C8 alkyl, aryl, or heteroaryl each optionally substituted by one or more halo, cyano, nitro, C1-C4 alkyl, C1-C4 haloallcyl, Cι-C4 alkoxy, or C1-C4 haloalkoxy; and R' is Ci-Cg alkyl; with a cyclizing reagent for a time and under conditions suitable for forming said compound of Formula II or salt form thereof.
29. The process of claim 28 wherein said cyclizing reagent comprises a Lewis acid.
30. The process of claim 28 wherein said cyclizing reagent comprises a Cι-C8 alkyl aluminum halide.
31. The process of claim 28 wherein said cyclizing reagent comprises a C2-C]6 dialkyl aluminum halide.
32. The process of claim 28 wherein said cyclizing reagent comprises A1C13.
33. The process of claim 28 wherein said cyclizing reagent comprises an acid.
34. The process of claim 28 wherein said cyclizing reagent comprises sulfuric acid.
35. The process of claim 28 wherein said reacting is carried out in the absence of solvent.
36. The process of claim 28 wherein said reacting is carried out in the presence of solvent.
37. The process of claim 28 wherein said reacting is carried out in a non-polar solvent.
38. The process of claim 28 wherein said reacting is carried out in a solvent comprising decahydronaphthalene or 1 ,2-dichlorobenzene.
39. The process of claim 28 wherein said reacting is carried out at elevated temperature.
40. The process of claim 28 wherein: ] R2 is Ci-Cg alkyl, -CH2-O-(CrC8 alkyl), C(O)O-(CrC8 allcyl), -C(O)NH-(Cι-C8 alkyl), OH, or
CH2OH; R3 and R6 are each H; R4 and R5 are each, independently, H, halo, Ci-Cg haloallcyl, hydroxy, OR9, SR9, alkoxyallcyl, NHR10, NR10RU, aryl, or heteroaryl, wherein said aryl can be substituted with up to two substituents selected from C]-C8 alkyl, halo, C C8 haloalkyl, and alkoxy, and said heteroaryl can be optionally substituted with up to two substituents selected from halogen and Cι-C8 alkyl; or R4 and R5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; R7a is H; R7b is H or Ci-Cg allcyl; R8a and R8b are each H; and R10 and R11 are each, independently, CrC8 alkyl, Cι-C8 alkenyl, Cι-C8 haloalkyl, aryl, heteroaryl, arallcyl, heteroarylalkyl, or allyl; provided that:
(A) if R2 is methyl and R4 is H, then R5 is not thiazole, substituted thiazole or a thiazole derivative; (B) if R7a is H and R7b is other than H, then neither R4 nor R5 can be H; (C) if R1 and R2 are methyl, and R5 is H then R4 is not NHR10 or NR10R' ' ; and (D) if R1 and R2 are methyl and R5 is H, then R4 is not imidazolyl, substituted imidazolyl, or an imidazole derivative.
41. The process of claim 40 wherein R1 is H.
42. The process of claim 40 wherein R1 is d-C8 allcyl.
43. The process of claim 40 wherein R2 is methyl, ethyl, n-propyl, or isopropyl.
44. The process of claim 40 wherein R2 is methyl.
45. The process of claim 40 wherein R4 is Cl, Br, haloallcyl, CF3, thiophenyl, furanyl, pyrrolyl, pyrazolyl, or imidazolyl.
46. The process of claim 40 wherein R4 is Cl.
47. The process of claim 40 wherein R5 is methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, or phenyl, wherein said imidazolyl is optionally substituted by one or more halo or methyl and said phenyl is optionally substituted with up to two substituents selected from Cι-C8 alkyl, d-C8 haloalkyl, halo, and alkoxy.
48. The process of claim 40 wherein R5 is H.
49. The process of claim 28 wherein: R2 is C1-C4 alkyl, -CH2-O-(d-C4 alkyl), C C4 haloallcyl, or CH2OH; R3 , R4, R5 , and R6 are each, independently, H, halo, C1-C4 alkyl, C1-C4 haloallcyl, hydroxy, NH2, CN, or NO2; and R7a ^ R7bj R8a ^ and RSb ^ ^ R. provided that: (H) when R2 is C,-C4 alkyl, -CH2-0-(CrC4 allcyl), or CH2OH, then R3 and R6 are not both H; and (I) when R2 is CH , then R3, R4, and R6 are each H and R5 is not H or isopropyl.
50. The process of claim 49 wherein R1 is H.
51. The process of claim 212 wherein R1 is Cι-C8 alkyl.
52. The process of claim 213 wherein R2 is CrC4 alkyl or C C4 haloallcyl.
53. The process of claim 214 wherein R2 is methyl, ethyl, isopropyl, n-butyl, or CF3.
54. The process of claim 49 wherein R3, R4, R5, and R6 are each, independently, H, methyl, NH2, CN, halo, CF3, N02, or OH.
55. The process of claim 28 wherein R7a, R7b, R8a, and R8b are each H.
56. The process of claim 28 wherein R3 and R6 are each H.
57. The process of claim 28 wherein R3, R5, and R6 are each H.
58. The process of claim 28 wherein R4 is halo.
59. The process of claim 28 wherein R4 is Cl. )
60. The process of claim 28 wherein R2 is C1-C4 alkyl.
61. The process of claim 28 wherein R2 is methyl.
62. The process of claim 28 wherein R1 is H.
63. The process of claim 28 wherein R1 is H or C C4 alkyl, R2 is CrC4 alkyl, R3 is H, R4 is halo, R5 is H, R6 is H, R7a is H, R7b is H, R8a is H, and R8b is H.
64. The process of claim 28 wherein R1 is H, R2 is Me, R3 is H, R4 is Cl, R5 is H, R6 is H, R7a is H, R7b is H, R8a is H, and R8b is H.
65. A process for preparing a compound of Formula I:
or salt form thereof, wherein: R1 is H or Ci-Cg alkyl; R2 is d-Cg alkyl, -CH2-O-(CrC8 alkyl), C(O)O-(C C8 alkyl), -C(O)NH-(C C8 allcyl), OH, C C4 haloallcyl, or CH2OH; R3 , R4, R5 , and R6 are each, independently, H, halo, C C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloallcyl, C C8 haloalkyl, hydroxy, mercapto, OR9, SR9, alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, hydroxyalkyl, NR10Rπ, CN, NO2, heterocycloallcyl, aryl, or heteroaryl, wherein said aryl and heteroaryl can be substituted with one or more substituents selected from d-C8 allcyl, halo, Cι-C8 haloallcyl, and alkoxy; or R4 and R5 together with the atoms to which they are attached form a 5- or 6- member heterocyclic ring having one O atom; R7a and R7b are each, independently, H, halo, d-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, C C8 haloalkyl, alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)0-alkyl, C(O)NH-alkyl, or hydroxyalkyl, or R and R >7b together with the carbon atom to which they are attached form a C3-C7 cycloallcyl group; R8a and R8b are each, independently, H, halo, Cι-C8 alkyl, C2-C8 alkenyl, d-Cs alkynyl, C3-C7 cycloallcyl, C C8 haloalkyl, alkoxyallcyl, hydroxy, C(O)-alkyl, C(O)O-allcyl, C(O)NH-alkyl, or hydroxyalkyl, or R8 and RSb together with the carbon atom to which they are attached form a C3-C7 cycloallcyl group; R9 is H, C]-C8 alkyl, C C8 alkenyl, Cι-C8 alkynyl, C3-C7 cycloalkyl, Cι-C8 haloalkyl, aralkyl, aryl, heteroaryl, heteroarylallcyl, or allyl; and R10 and R11 are each, independently, H, Cι-C8 allcyl, Cι-C8 alkenyl, Cι-C8 alkynyl, C3-C7 cycloalkyl, Cι-C8 haloallcyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R10 and R11 together with the N atom to which they are attached form a heterocyclic ring; comprising: (a) reacting a compound of Formula III:
III or salt form thereof, wherein: L is halo, hydroxy, C C8 alkoxy, Cι-C8 thioalkoxy, Ci-Cg acyloxy, -OSO2R, or -OSi(R')3; R is CpCg alkyl, aryl, or heteroaryl each optionally substituted by one or more halo, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, or C1-C4 haloalkoxy; and R' is Ci-Cg alkyl; with a cyclizing reagent for a time and under conditions suitable for forming a compound of Formula II:
II or salt form thereof; and (b) reacting said compound of Formula II or salt form thereof with a reducing agent optionally in the presence of a Lewis acid for a time and under conditions suitable for forming said compound of Formula I or salt form thereof.
66. The process of claim 65 wherein said cyclizing reagent comprises a Lewis acid.
67. The process of claim 65 wherein said cyclizing reagent comprises a Ci-Cg alkyl aluminum halide.
68. The process of claim 65 wherein said cyclizing reagent comprises a C2-C16 diallcyl aluminum halide.
69. The process of claim 65 wherein said cyclizing reagent comprises A1C13.
70. The process of claim 65 wherein said cyclizing reagent comprises an acid.
71. The process of claim 65 wherein said cyclizing reagent comprises sulfuric acid.
72. The process of claim 65 wherein said reacting of step a) is carried out in the absence of solvent.
73. The process of claim 65 wherein said reacting of step a) is carried out in the presence of solvent.
74. The process of claim 65 wherein said reacting of step a) is carried out in a non-polar solvent.
75. The process of claim 65 wherein said reacting of step a) is carried out in a solvent comprising decahydronaphthalene or 1,2-dichlorobenzene.
76. The process of claim 65 wherein said reducing agent comprises a borane.
77. The process of claim 65 wherein said reducing agent comprises BH3.
78. The process of claim 65 wherein said reducing agent comprises a metal hydride.
79. The process of claim 65 wherein said reducing agent comprises a borohydride or aluminum hydride.
80. The process of claim 65 wherein: R2 is d-Cg alkyl, -CH2-O-(d-Cg allcyl), C(O)O-(C,-C8 allcyl), -C(O)NH-(C Cg alkyl), OH, or CH2OH; R3 and R6 are each H; R4 and R5 are each, independently, H, halo, C Cg haloalkyl, hydroxy, OR9, SR9, alkoxyalkyl, NHR10, NR10RU, aryl, or heteroaryl, wherein said aryl can be substituted with up to two substituents selected from Ci-Cg alkyl, halo, Ci-Cg haloallcyl, and alkoxy, and said heteroaryl can be optionally substituted with up to two substituents selected from halogen and Cι-C8 alkyl; or R4 and R5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; R7a is H; R7 is H or Ci-Cg alkyl; R8a and R8b are each H; and R10 and R11 are each, independently, C C8 alkyl, Ci-Cg alkenyl, Ci-Cg haloalkyl, aryl, heteroaryl, arallcyl, heteroarylallcyl, or allyl; provided that:
(A) if R2 is methyl and R4 is H, then R5 is not thiazole, substituted thiazole or a thiazole derivative; (B) if R7a is H and R7b is other than H, then neither R4 nor R5 can be H; (C) ifR1 and R2 are methyl, and R5 is H then R4 is not NHR10 or NR10Rn; and (D) ifR1 and R2 are methyl and R5 is H, then R4 is not imidazolyl, substituted imidazolyl, or an imidazole derivative.
81. The process of claim 80 wherein R2 is methyl, ethyl, n-propyl, or isopropyl.
82. The process of claim 80 wherein R2 is methyl.
83. The process of claim 80 wherein R4 is Cl, Br, haloallcyl, CF3, thiophenyl, furanyl, pyrrolyl, pyrazolyl, or imidazolyl.
84. The process of claim 80 wherein R4 is Cl.
85. The process of claim 80 wherein R5 is methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, or phenyl, wherein said imidazolyl is optionally substituted by one or more halo or methyl and said phenyl is optionally substituted with up to two substituents selected from Ci-Cg alkyl, Ci-Cg haloalkyl, halo, and alkoxy.
86. The process of claim 80 wherein R5 is H.
87. The process of claim 65 wherein: R2 is CrC4 alkyl, -CH2-O-(C,-C4 alkyl), Cj-C4 haloallcyl, or CH2OH; R3 , R4, R5 , and R6 are each, independently, H, halo, Cι-C4 alkyl, CrC4 haloallcyl, hydroxy, NH2, CN, or NO2; and R7a ^ R7b? RSa ^ ^ RSb & Q ^ pj. provided that: (H) when R2 is CrC4 alkyl, -CH2-O-(d-C4 alkyl), or CH2OH, then R3 and Rδ are not both H; and (I) when R2 is CH3, then R3, R4, and R6 are each H and R5 is not H or isopropyl.
88. The process of claim 65 wherein R7a, R7b, R8a, and R8b are each H.
89. The process of claim 65 wherein R3 and R6 are each H.
90. The process of claim 65 wherein R3, R5, and R6 are each H.
91. The process of claim 65 wherein R4 is halo.
92. The process of claim 65 wherein R4 is Cl.
93. The process of claim 65 wherein R2 is C1-C4 allcyl.
94. The process of claim 65 wherein R2 is methyl.
95. The process of claim 65 wherein R1 is H.
96. The process of claim 65 wherein R1 is H or C,-C4 alkyl, R2 is CrC4 allcyl, R3 is H, R4 is halo, R5 is H, R6 is H, R7a is H, R7b is H, R8a is H, and R8b is H.
97. The process of claim 65 wherein R1 is H, R2 is Me, R3 is H, R4 is Cl, R5 is H, R6 is H, R7a is H, R7b is H, R8a is H, and R8b is H.
98. The process of claim 65 wherein said compound of Formula I has an S configuration at the carbon bearing R2.
99. The process of claim 65 wherein said compound of Formula I has an R configuration at the carbon bearing R2.
100. A process for preparing a compound of Formula I:
or salt form thereof, wherein: R1 is H or Ci-Cg alkyl; R2 is Ci-Cg alkyl, -CH2-0-(C,-C8 alkyl), C(O)O-(CrC8 allcyl), -C(O)NH-(C,-C8 alkyl), OH, Ci- C4 haloallcyl, or CH2OH;
'"' Rτ, R4, R5 , and R6 are each, independently, H, halo, C C8 allcyl, C2-C8 alkenyl, C2-C8 alkynyl,
C3-C7 cycloallcyl, d-C8 haloallcyl, hydroxy, mercapto, OR9, SR9, alkoxyalkyl, C(0)-alkyl, C(O)O-alkyl, C(0)NH-alkyl, hydroxyallcyl, NR10Rn, CN, N02, heterocycloallcyl, aryl, or heteroaryl, wherein said aryl and heteroaryl can be substituted with one or more substituents selected from C C8 alkyl, halo, Cι-C8 haloallcyl, and alkoxy; or R4 and R5 together with the atoms to which they are attached form a 5- or 6- ember heterocyclic ring having one O atom; R7a and R7b are each, independently, H, halo, CrC8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, CrC8 haloalkyl, alkoxyalkyl, hydroxy, C(O)-alkyl, C(0)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, or R7a and R7b together with the carbon atom to which they are attached form a C3-C7 cycloalkyl group; RSa and R8b are each, independently, H, halo, CrC8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, C C8 haloallcyl, alkoxyalkyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(0)NH-alkyl, or hydroxyallcyl, or R8a and R8b together with the carbon atom to which they are attached form a C3-C7 cycloalkyl group; R9 is H, d-Cg alkyl, C C8 alkenyl, CrC8 alkynyl, C3-C7 cycloalkyl, C C8 haloalkyl, aralkyl, aryl, heteroaryl, heteroarylallcyl, or allyl; and R10 and R11 are each, independently, H, d-C8 alkyl, C C8 alkenyl, C]-C8 alkynyl, C3-C7 cycloallcyl, C]-C8 haloalkyl, arallcyl, aryl, heteroaryl, heteroarylallcyl, or allyl, or R10 and R11 together with the N atom to which they are attached form a heterocyclic ring; comprising: (a) reacting a compound of Formula IN:
rv or salt form thereof, with a compound of Formula:
wherein: L is halo, hydroxy, Cι-C8 alkoxy, Cι-C8 thioalkoxy, Cι-C8 acyloxy, -OS02R, or -OSi(R')3;
R is Cι-C8 alkyl, aryl, or heteroaryl each optionally substituted by one or more halo, cyano, nitro, C1-C4 alkyl, C C4 haloallcyl, CrC4 alkoxy, or C1-C4 haloalkoxy; W is Cι-C8 allcyl; and Q is a leaving group, for a time and under conditions suitable for forming a compound of Formula III:
III or salt form thereof; (b) reacting said compound of Formula III or salt form thereof, with a cyclizing reagent for a time and under conditions suitable for forming a compound of Formula II:
II or salt form thereof; and (c) reacting said compound of Formula II with a reducing agent optionally in the presence of a Lewis acid for a time and under conditions suitable for forming said compound of Formula I or salt form thereof.
101. The process of claim 100 wherein Q is hydroxy, alkoxy, halo, or O(CO)RQ, wherein RQ is Cι-C8 allcyl, C3-C7 cycloalkyl, aryl, heteroaryl, or heterocycloallcyl.
102. The process of claim 100 wherein Q is halo.
103. The process of claim 100 wherein Q is Cl.
104. The process of claim 100 wherein then reacting of step (a) is carried out in the presence of base.
105. The process of claim 100 wherein said cyclizing reagent comprises a Lewis acid.
106. The process of claim 100 wherein said cyclizing reagent comprises a CrC8 allcyl aluminum halide.
107. The process of claim 100 wherein said cyclizing reagent comprises a C2-Cι6 dialkyl aluminum halide.
108. The process of claim 100a wherein said cyclizing reagent comprises A1C13.
109. The process of claim 100 wherein said cyclizing reagent comprises an acid.
110. The process of claim 100 wherein said cyclizing reagent comprises sulfuric acid.
111. The process of claim 100 wherein said reacting of step b) is carried out in the absence of solvent.
112. The process of claim 100 wherein said reacting of step b) is carried out in the presence of solvent.
113. The process of claim 100 wherein said reacting of step b) is carried out in a non-polar solvent.
114. The process of claim 100 wherein said reacting of step b) is carried out in a solvent comprising decahydronaphthalene or 1,2-dichlorobenzene.
115. The process of claim 100 wherein said reducing agent comprises a borane.
116. The process of claim 100 wherein said reducing agent comprises BH3.
117. The process of claim 100 wherein said reducing agent comprises a metal hydride.
118. The process of claim 100 wherein said reducing agent comprises a borohydride or aluminum hydride.
119. The process of claim 100 wherein: R2 is Ci-Cg alkyl, -CH2-0-(d-C8 alkyl), C(O)O-(C,-C8 allcyl), -C(O)NH-(d-C8 alkyl), OH, or CH2OH; R and R are each H; R and R are each, independently, H, halo, C C8 haloalkyl, hydroxy, OR , SR , alkoxyalkyl. NHR10, NR10Rn, aryl, or heteroaryl, wherein said aryl can be substituted with up to two substituents
selected from Ci-Cg alkyl, halo, Cι-C8 haloallcyl, and alkoxy, and said heteroaryl can be optionally substituted with up to two substituents selected from halogen and CrC8 allcyl; or R4 and R5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; R7a is H; R7b is H or Ci-Cg allcyl; R8a and R8b are each H; and R10 and R11 are each, independently, d-Cg alkyl, Cι-C8 alkenyl, Cι-C8 haloallcyl, aryl, heteroaryl, arallcyl, heteroarylallcyl, or allyl; provided that: (A) if R2 is methyl and R4 is H, then R5 is not thiazole, substituted thiazole or a thiazole derivative; (B) if R7a is H and R7 is other than H, then neither R4 nor R5 can be H; (C) ifR1 and R2 are methyl, and R5 is H then R4 is not NHR10 or NR10Rπ; and (D) ifR1 and R2 are methyl and R5 is H, then R4 is not imidazolyl, substituted imidazolyl, or an imidazole derivative.
120. The process of claim 119 wherein R2 is methyl, ethyl, n-propyl, or isopropyl.
121. The process of claim 119 wherein R2 is methyl.
122. The process of claim 119 wherein R4 is Cl, Br, haloalkyl, CF3, thiophenyl, furanyl, pyrrolyl, pyrazolyl, or imidazolyl.
123. The process of claim 119 wherein R4 is Cl.
124. The process of claim 119 wherein R5 is methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, or phenyl, wherein said imidazolyl is optionally substituted by one or more halo or methyl and said phenyl is optionally substituted with up to two substituents selected from d-C8 alkyl, Cι-C8 haloallcyl, halo, and alkoxy.
125. The process of claim 119 wherein R5 is H.
126. The process of claim 100 wherein: R2 is Cι-C4 alkyl, -CH2-O-(d-C4 alkyl), CrC4 haloallcyl, or CH2OH; R3 , R4, R5 , and R6 are each, independently, H, halo, C1-C4 alkyl, Cι-C4 haloallcyl, hydroxy, NH2, CN, or NO2; and R7a s R7b} R8a ^ ^ R8b &χQ each R. provided that:
(H) when R2 is C,-C4 allcyl, -CH2-O-(CrC4 allcyl), or CH2OH, then R3 and R6 are not both H; and (I) when R2 is CH3, then R3, R4, and R6 are each H and R5 is not H or isopropyl.
127. The process of claim 100 wherein R7a, R7b, R8a, and R8b are each H.
128. The process of claim 100 wherein R3 and R6 are each H.
129. The process of claim 100 wherein R3, R5, and R6 are each H.
130. The process of claim 100 wherein R4 is halo.
131. The process of claim 100 wherein R4 is Cl.
132. The process of claim 100 wherein R2 is Cι-C4 alkyl.
133. The process of claim 100 wherein R2 is methyl.
134. The process of claim 100 wherein R1 is H.
135. The process of claim 100 wherein R1 is H or CrC4 alkyl, R2 is C C4 allcyl, R3 is H, R4 is halo, R5 is H, R6 is H, R7a is H, R7b is H, R8a is H, and R8b is H.
136. The process of claim 100 wherein R1 is H, R2 is Me, R3 is H, R4 is Cl, R5 is H, R6 is H, R7a is H, R7b is H, R8a is H, and R8b is H.
137. The process of claim 100 wherein said compound of Formula I has an S configuration at the carbon bearing R2.
138. The process of claim 100 wherein said compound of Formula I has an R configuration at the carbon bearing R2.
139. A process for preparing a compound of Formula I:
or salt form thereof, wherein: R1 is H or d-Cg alkyl; R2 is Ci-Cg alkyl, -CH2-O-(C C8 alkyl), C(O)0-(CrC8 allcyl), -C(O)NH-(CrC8 alkyl), OH, C,- C4 haloallcyl, or CH2OH; R3 , R4, R5 , and R6 are each, independently, H, halo, Cι-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloallcyl, d-Cg haloallcyl, hydroxy, mercapto, OR9, SR9, alkoxyalkyl, C(O)-alkyl, C(O)0-allcyl, C(O)NH-alkyl, hydroxyalkyl, NR10Rπ, CN, NO2, heterocycloalkyl, aryl, or heteroaryl, wherein said aryl and heteroaryl can be substituted with one or more substituents selected from Cj-C8 alkyl, halo, Cι-C8 haloalkyl, and alkoxy; or R4 and R5 together with the atoms to which they are attached form a 5- or 6- member heterocyclic ring having one O atom; R and R ,7b are,each, independently, H, halo, Cι-C8 alkyl, C2-C8 alkenyl, C2-Cg alkynyl, C3-d cycloallcyl, CrCg haloalkyl, alkoxyallcyl, hydroxy, C(O)-alkyl, C(0)O-alkyl, C(0)NH-alkyl, or hydroxyallcyl, or R7a and R7b together with the carbon atom to which they are attached form a C3-C7 cycloallcyl group; R8a and R8b are each, independently, H, halo, C C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, CrC8 haloallcyl, alkoxyallcyl, hydroxy, C(O)-alkyl, C(0)0-alkyl, C(0)NH-alkyl, or hydroxyallcyl, or R8a and R8b together with the carbon atom to which they are attached form a C3-C7 cycloalkyl group; R9 is H, Cι-C8 alkyl, C C8 alkenyl, CrC8 alkynyl, C3-C7 cycloallcyl, CrC8 haloalkyl, aralkyl, aryl, heteroaryl, heteroarylallcyl, or allyl; and R10 and Rπ are each, independently, H, CrC8 alkyl, CrC8 alkenyl, Cι-C8 alkynyl, C3-C7 cycloalkyl, C C8 haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R10 and R11 together with the N atom to which they are attached form a heterocyclic ring; comprising reacting a compound of Formula Ilia:
Ilia wherein: L is halo, hydroxy, Ci-Cg alkoxy, Cι-C8 thioalkoxy, Cι-C8 acyloxy, -OS02R, or
-OSi(R')3; R is Cι-C8 alkyl, aryl, or heteroaryl each optionally substituted by one or more halo, cyano, nitro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, or C1-C4 haloalkoxy; and R' is Cι-C8 alkyl; with a cyclizing reagent for a time and under conditions suitable for forming said compound of Formula I.
140. The process of claim 139 wherein said cyclizing
Lewis acid.
141. The process of claim 139 wherein said cyclizing reagent comprises a Cι-C8 alkyl aluminum halide.
142. The process of claim 139 wherein said cyclizing reagent comprises a C2-C]6 diallcyl aluminum halide.
143. The process of claim 139 wherein said cyclizing reagent comprises A1C1 .
144. The process of claim 139 wherein said cyclizing reagent comprises an acid.
145. The process of claim 139 wherein said cyclizing reagent comprises sulfuric acid.
146. The process of claim 139 wherein said reacting is carried out in the absence of solvent.
147. The process of claim 139 wherein said reacting is carried out in the presence of solvent.
148. The process of claim 139 wherein said reacting is carried out in a non-polar solvent.
149. The process of claim 139 wherein said reacting is carried out in a solvent comprising decahydronaphthalene or 1,2-dichlorobenzene.
150. The process of claim 139 wherein said reacting is carried out at elevated temperature.
151. The process of claim 139 wherein: R2 is C,-Cg allcyl, -CH2-0-(CrC8 alkyl), C(0)0-(Cι-C8 alkyl), -C(O)NH-(CrC8 alkyl), OH, or CH2OH; R3 and R6 are each H; R4 and R5 are each, independently, H, halo, CrC8 haloallcyl, hydroxy, OR9, SR9, alkoxyalkyl, NHR10, NR10Rπ, aryl, or heteroaryl, wherein said aryl can be substituted with up to two substituents selected from C C8 alkyl, halo, C]-C8 haloallcyl, and alkoxy, and said heteroaryl can be optionally substituted with up to two substituents selected from halogen and Cι-C8 alkyl; or R4 and R5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; R7a is H; R7b is H or Cι-C8 alkyl; R8a and R8b are each H; and R10 and R11 are each, independently, Cι-C8 allcyl, C C8 alkenyl, C C8 haloallcyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, or allyl; provided that: (A) ifR2 is methyl and R4 is H, then R5 is not thiazole, substituted thiazole or a thiazole derivative; (B) if R7a is H and R7b is other than H, then neither R4 nor R5 can be H; (C) ifR1 and R2 are methyl, and R5 is H then R4 is not NHR10 or NR10Rπ; and (D) ifR1 and R2 are methyl and R5 is H, then R4 is not imidazolyl, substituted imidazolyl, or an imidazole derivative.
152. The process of claim 151 wherein R1 is H.
153. The process of claim 151 wherein R1 is Cι-C8 alkyl.
154. The process of claim 151 wherein R 2 . is methyl, ethyl, n-propyl, or isopropyl
155. The process of claim 151 wherein R2 is methyl.
156. The process of claim 151 wherein R4 is Cl, Br, haloallcyl, CF3, thiophenyl, furanyl, pyrrolyl, pyrazolyl, or imidazolyl.
157. The process of claim 151 wherein R4 is Cl.
158. The process of claim 151 wherein R5 is methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, or phenyl, wherein said imidazolyl is optionally substituted by one or more halo or methyl and said phenyl is optionally substituted with up to two substituents selected from Cι-C8 allcyl, C]-C8 haloalkyl, halo, and alkoxy.
159. The process of claim 151 wherein R5 is H.
160. The process of claim 139 wherein: R2 is Cι-C4 alkyl, -CH2-O-(d-C4 alkyl), C C4 haloallcyl, or CH2OH; R3 , R4, R5 , and R6 are each, independently, H, halo, C1-C4 alkyl, Cι-C4 haloalkyl, hydroxy, NH2, CN, orN02; and R7a ^ R7bj R8a ^ ^ R8b ^ each JJ. provided that (H) when R2 is C,-C4 allcyl, -CH2-0-(CrC4 alkyl), or CH2OH, then R3 and R6 are not both H; and (I) when R2 is CH3, then R3, R4, and R6 are each H and R5 is not H or isopropyl.
161. The process of claim 160 wherein R1 is H.
162. The process of claim 160 wherein R1 is Ci-Cg alkyl.
163. The process of claim 160 wherein R2 is C1-C4 alkyl or C1-C4 haloallcyl.
164. The process of claim 160 wherein R2 is methyl, ethyl, isopropyl, n-butyl, or CF3.
165. The process of claim 160 wherein R3, R4, R5, and R6 are each, independently, H, methyl, NH2, CN, halo, CF3, N02, or OH.
166. The process of claim 139 wherein R7 , R7b, R8a, and R8b are each H.
167. The process of claim 139 wherein R3 and R6 are each H.
168. The process of claim 139 wherein R3, R5, and R6 are each H.
169. The process of claim 139 wherein R4 is halo.
170. The process of claim 139 wherein R4 is Cl.
171. The process of claim 139 wherein R2 is Cι-C4 alkyl.
172. The process of claim 139 wherein R2 is methyl.
173. The process of claim 139 wherein R1 is H.
174. The process of claim 139 wherein R1 is H or CrC4 alkyl, R2 is CrC4 allcyl, R3 is H, R4 is halo, R5 is H, R6 is H, R7a is H, R7b is H, R8a is H, and R8b is H.
175. The process of claim 139 wherein R1 is H, R2 is Me, R3 is H, R4 is Cl, R5 is H, R6 is H, R7a is H, R7b is H, R8a is H, and R8b is H.
176. A process for preparing a compound of Formula Ilia:
or salt form thereof, wherein: R1 is H or Ci-Cg alkyl; R2 is Ci-Cg alkyl, -CH2-0-(Cι-C8 alkyl), C(0)0-(C C8 allcyl), -C(O)NH-(C C8 alkyl), OH, C C haloallcyl, or CH2OH; R3 , R4, R5 , and R6 are each, independently, H, halo, d-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloallcyl, CrC8 haloalkyl, hydroxy, mercapto, OR9, SR9, alkoxyalkyl, C(O)-alkyl, C(0)0-alkyl, C(O)NH-alkyl, hydroxyalkyl, NR10Rn, CN, N02, heterocycloalkyl, aryl, or heteroaryl, wherein said aryl and heteroaryl can be substituted with one or more substituents selected from -d alkyl, halo, d-C8 haloalkyl, and alkoxy; or R4 and R5 together with the atoms to which they are attached form a 5- or 6- member heterocyclic ring having one O atom; R7a and R7b are each, independently, H, halo, CrC8 allcyl, C2-Cg alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, d-d haloalkyl, alkoxyallcyl, hydroxy, C(0)-alkyl, C(0)0-alkyl, C(0)NH-alkyl, or hydroxyallcyl, or R7a and R7b together with the carbon atom to which they are attached form a C3-C7 cycloallcyl group; R8a and R8b are each, independently, H, halo, Cι-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloallcyl, CrC8 haloallcyl, alkoxyallcyl, hydroxy, C(O)-alkyl, C(0)0-alkyl, C(0)NH-alkyl, or
hydroxyalkyl, or R8a and R8b together with the carbon atom to which they are attached form a C3-C7 cycloallcyl group; R9 is H, Cι-C8 alkyl, Ci-Cg alkenyl, d-C8 alkynyl, C3-C7 cycloallcyl, C C8 haloallcyl, aralkyl, aryl, heteroaryl, heteroarylallcyl, or allyl; R10 and R11 are each, independently, H, CrC8 alkyl, C Cs alkenyl, CrC8 alkynyl, C3-C7 cycloalkyl, Cι-C8 haloallcyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R10 and R11 together with the N atom to which they are attached form a heterocyclic ring; L is halo, hydroxy, Cι-C8 alkoxy, C C8 thioalkoxy, C C8 acyloxy, -OS02R, or
-OSi(R') ; R is Ci-Cg alkyl, aryl, or heteroaryl each optionally substituted by one or more halo, cyano, nitro, C1-C4 alkyl, d-C4 haloalkyl, C1-C4 alkoxy, or C1-C4 haloalkoxy; and R' is Cι-C8 allcyl; comprising reacting a compound of Formula HI:
with a reducing agent optionally in the presence of a Lewis acid for a time and under conditions suitable for forming said compound of Formula Ilia.
177. The process of claim 176 wherein the stereochemistry of chiral centers present in said compound of Formula Ilia is retained in said compound of Formula III.
178. The process of claim 176 wherein said reducing agent comprises a borane.
179. The process of claim 176 wherein said reducing agent comprises BH3.
180. The process of claim 176 wherein said reducing agent comprises a metal hydride.
181. The process of claim 176 wherein said reducing agent comprises a borohydride or aluminum hydride.
182. The process of claim 176 wherein:
R2 is Ci-Cg allcyl, -CH2-O-(d-C8 allcyl), C(0)O-(C C8 alkyl), -C(O)NH-(C C8 alkyl), OH, or
CH2OH; R3 and R6 are each H; R4 and R5 are each, independently, H, halo, Cι-C8 haloalkyl, hydroxy, OR9, SR9, alkoxyallcyl, NHR10, NR10Rπ, aryl, or heteroaryl, wherein said aryl can be substituted with up to two substituents selected from C C8 alkyl, halo, Cι-C8 haloallcyl, and alkoxy, and said heteroaryl can be optionally substituted with up to two substituents selected from halogen and C C8 allcyl; or R4 and R5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; R7a is H; R7b is H or Cι-C8 alkyl; R8a and R8b are each H; and R10 and R11 are each, independently, Cι-C8 allcyl, Cι-C8 alkenyl, Cι-C8 haloalkyl, aryl, heteroaryl, arallcyl, heteroarylallcyl, or allyl; provided that: (A) ifR2 is methyl and R4 is H, then R5 is not thiazole, substituted thiazole or a thiazole derivative; (B) if R7a is H and R7b is other than H, then neither R4 nor R5 can be H; (C) ifR1 and R2 are methyl, and R5 is H then R4 is not NHR10 or NR10Rn; and (D) ifR1 and R2 are methyl and R5 is H, then R4 is not imidazolyl, substituted imidazolyl, or an imidazole derivative.
183. The process of claim 182 wherein R1 is H.
184. The process of claim 182 wherein R1 is d-Cg alkyl.
185. The process of claim 182 wherein R2 is methyl, ethyl, n-propyl, or isopropyl.
186. The process of claim 182 wherein R2 is methyl.
187. The process of claim 182 wherein R4 is Cl, Br, haloalkyl, CF3, thiophenyl, furanyl, pyrrolyl, pyrazolyl, or imidazolyl.
188. The process of claim 182 wherein R4 is Cl.
189. The process of claim 182 wherein R5 is methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, or phenyl, wherein said imidazolyl is optionally substituted by one or more halo or methyl and said phenyl is optionally substituted with up to two substituents selected from Ci-Cg alkyl, Cι-C8 haloallcyl, halo, and alkoxy.
1 0. The process of claim 182 wherein R5 is H.
1 1. The process of claim 176 wherein: R2 is Cι-C4 alkyl, -CH2-0-(C C4 alkyl), C C4 haloallcyl, or CH2OH; R3 , R4, R5 , and R6 are each, independently, H, halo, C C4 alkyl, C C4 haloallcyl, hydroxy, NH2, CN, or N02; and R7a 3 R7bj R8a ^ and R8b ^ gach H; provided that: (H) when R2 is CrC4 alkyl, -CH2-0-(CrC4 allcyl), or CH2OH, then R3 and R6 are not both H; and (I) when R2 is CH3, then R3, R4, and R6 are each H and R5 is not H or isopropyl.
192. The process of claim 191 wherein R1 is H.
193. The process of claim 191 wherein R1 is Cι-C8 alkyl.
194. The process of claim 191 wherein R2 is C1-C4 alkyl or d-C4 haloallcyl.
195. The process of claim 191 wherein R2 is methyl, ethyl, isopropyl, n-butyl, or CF3.
196. The process of claim 191 wherein R3, R4, R5, and R6 are each, independently, H, methyl, NH2, CN, halo, CF3, N02, or OH.
197. The process of claim 176 wherein R7a, R7b, R8a, and R8b are each H.
198. The process of claim 176 wherein R3 and R6 are each H.
199. The process of claim 176 wherein R3, R5, and R6 are each H.
176. The process of claim 176 wherein R4 is halo.
201. The process of claim 176 wherein R4 is Cl.
202. The process of claim 176 wherein R2 is C1-C4 allcyl.
203. The process of claim 176 wherein R2 is methyl.
204. The process of claim 176 wherein R is H.
205. The process of claim 176 wherein R1 is H or CrC4 allcyl, R2 is CrC4 allcyl, R3 is H, R4 is halo, R5 is H, R" is H, R/a is H, R/D is H, Rsa is H, and W 8b° is H
206. The process of claim 176 wherein R1 is H, R2 is Me, R3 is H, R4 is Cl, R5 is H, R6 is H, R7a is H, R7b is H, R8a is H, and R8b is H.
207. A process for preparing a compound of Formula I:
or salt form thereof, wherein: R1 is H or C,-C8 alkyl; R2 is CrC8 alkyl, -CH2-0-(C,-C8 alkyl), C(0)0-(CrC8 allcyl), -C(O)NH-(C C8 alkyl), OH, C C4 haloalkyl, or CH2OH; R3 , R4, R5 , and R6 are each, independently, H, halo, Cι-C8 alkyl, C2-Cg alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, d-Cg haloallcyl, hydroxy, mercapto, OR9, SR9, alkoxyallcyl, C(0)-alkyl, C(0)0-alkyl, C(O)NH-alkyl, hydroxyallcyl, NR10Rn, CN, NO2, heterocycloallcyl, aryl, or heteroaryl, wherein said aryl and heteroaryl can be substituted with one or more substituents selected from C]-C8 alkyl, halo, Ci-Cg haloallcyl, and alkoxy; or R4 and R5 together with the atoms to which they are attached form a 5- or 6- member heterocyclic ring having one O atom; R7a and R7b are each, independently, H, halo, Ci-Cg allcyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloallcyl, Ci-Cg haloalkyl, alkoxyalkyl, hydroxy, C(0)-alkyl, C(0)0-alkyl, C(0)NH-alkyl, or hydroxyalkyl, or R a and R together with the carbon atom to which they are attached form a C3-C7 cycloallcyl group; R8a and R8b are each, independently, H, halo, Ci-Cg alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, C,-C8 haloalkyl, alkoxyallcyl, hydroxy, C(0)-alkyl, C(0)0-alkyl, C(0)NH-alkyl, or hydroxyallcyl, or R8a and R8b together with the carbon atom to which they are attached form a C3-C7 cycloallcyl group; R9 is H, d-Cg alkyl, C,-Cg alkenyl, Ci-Cg alkynyl, C3-C7 cycloalkyl, Ci-Cg haloalkyl, aralkyl, aryl, heteroaryl, heteroarylallcyl, or allyl;
R10 and R11 are each, independently, H, d-C8 allcyl, CrC8 alkenyl, Cι-C8 alkynyl, C3-C7 cycloalkyl, CpCg haloallcyl, arallcyl, aryl, heteroaryl, heteroarylallcyl, or allyl, or R10 and R11 together with the N atom to which they are attached form a heterocyclic ring; comprising a) reacting a compound of Formula III:
III wherein: L is halo, hydroxy, Cι-C8 alkoxy, Cι-C8 thioalkoxy, Ci-Cg acyloxy, -OS02R, or -OSi(R')3; R is Cι-C8 allcyl, aryl, or heteroaryl each optionally substituted by one or more halo, cyano, nitro, C1-C4 allcyl, C C haloalkyl, C1-C4 alkoxy, or C]-C4 haloalkoxy; and R' is CrC8 alkyl; with a reducing agent optionally in the presence of a Lewis acid for a time and under conditions suitable for forming a compound of Formula Ilia:
Ilia and b) reacting said compound of Formula Ilia with a cyclizing reagent for a time and under conditions suitable for forming said compound of Formula I.
208. The process of claim 207 wherein the stereochemistry of chiral centers present in said compound of Formula III is retained.
209. The process of claim 207 wherein said reducing agent comprises a borane.
210. The process of claim 207 wherein said reducing agent comprises BH3.
211. The process of claim 207 wherein said reducing agent comprises a metal hydride.
212. The process of claim 207 wherein said reducing agent comprises a borohydride or aluminum hydride.
213. The process of claim 207 wherein said cyclizing reagent comprises a Lewis acid.
214. The process of claim 207 wherein said cyclizing reagent comprises a Ci-Cg alkyl aluminum halide.
215. The process of claim 207 wherein said cyclizing reagent comprises a C2-d6 diallcyl aluminum halide.
216. The process of claim 207 wherein said cyclizing reagent comprises AICI3.
217. The process of claim 207 wherein said cyclizing reagent comprises an acid.
218. The process of claim 207 wherein said cyclizing reagent comprises sulfuric acid.
219. The process of claim 207 wherein said reacting of step b) is carried out in the absence of solvent.
220. The process of claim 207 wherein said reacting of step b) is carried out in the presence of solvent.
221. The process of claim 207 wherein said reacting of step b) is carried out in a non-polar solvent.
222. The process of claim 207 wherein said reacting of step b) is carried out in a solvent comprising decahydronaphthalene or 1,2-dichlorobenzene.
223. The process of claim 207 wherein: R2 is Ci-Cg allcyl, -CH2-O-(d-C8 alkyl), C(0)0-(C,-CS alkyl), -C(0)NH-(CrCg allcyl), OH, or CH2OH; R3 and R6 are each H; R4 and R5 are each, independently, H, halo, Cj-Cg haloallcyl, hydroxy, OR9, SR9, alkoxyalkyl, NHR10, NR10Rπ, aryl, or heteroaryl, wherein said aryl can be substituted with up to two substituents selected from Ci-Cg alkyl, halo, Cι-C8 haloallcyl, and alkoxy, and said heteroaryl can be optionally
substituted with up to two substituents selected from halogen and CrCg allcyl; or R4 and R5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; R7a is H; R7b is H or Ci-Cg alkyl; R8a and R8b are each H; and R10 and Ru are each, independently, Cι-C8 allcyl, Cι-C8 alkenyl, d-C8 haloalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, or allyl; provided that: (A) ifR2 is methyl and R4 is H, then R5 is not thiazole, substituted thiazole or a thiazole derivative; (B) if R7a is H and R7b is other than H, then neither R4 nor R5 can be H; (C) if R1 and R2 are methyl, and R5 is H then R4 is not NHR10 or NR^R1 ' ; and (D) ifR1 and R2 are methyl and R5 is H, then R4 is not imidazolyl, substituted imidazolyl, or an imidazole derivative.
224. The process of claim 223 wherein R1 is H.
225. The process of claim 223 wherein R1 is d-C8 allcyl.
226. The process of claim 223 wherein R2 is methyl, ethyl, n-propyl, or isopropyl.
227. The process of claim 223 wherein R2 is methyl.
228. The process of claim 223 wherein R4 is Cl, Br, haloallcyl, CF3, thiophenyl, furanyl, pyrrolyl, pyrazolyl, or imidazolyl.
229. The process of claim 223 wherein R4 is Cl.
230. The process of claim 223 wherein R5 is methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, or phenyl, wherein said imidazolyl is optionally substituted by one or more halo or methyl and said phenyl is optionally substituted with up to two substituents selected from Cι-C8 alkyl, Cι-C8 haloalkyl, halo, and al oxy.
231. The process of claim 223 wherein R5 is H.
232. The process of claim 207 wherein: R2 is Ci-C4 allcyl, -CH2-0-(CrC4 alkyl), C1-C4 haloalkyl, or CH2OH;
R3 , R4, R5 , and R6 are each, independently, H, halo, CrC4 allcyl, C C4 haloallcyl, hydroxy, NH2, CN, or NO2; and R7a ^ R7b) RSa ^ md R8b ^ g^ R. provided that: (TT) when R2 is d-C4 alkyl, -CH2-0-(C C4 alkyl), or CH2OH, then R3 and R6 are not both H; and (I) when R2 is CH3, then R3, R4, and R6 are each H and R5 is not H or isopropyl.
233. The process of claim 232 wherein R1 is H.
234. The process of claim 232 wherein R1 is d-C8 alkyl.
235. The process of claim 232 wherein R2 is C1-C4 alkyl or C1-C4 haloallcyl.
236. The process of claim 232 wherein R2 is methyl, ethyl, isopropyl, n-butyl, or CF3.
237. The process of claim 232 wherein R3, R4, R5, and R6 are each, independently, H, methyl, NH2, CN, halo, CF3, N02, or OH.
238. The process of claim 207 wherein R7a, R7b, R8a, and R8b are each H.
239. The process of claim 207 wherein R3 and R6 are each H.
240. The process of claim 207 wherein R3, R5, and R6 are each H.
241. The process of claim 207 wherein R4 is halo.
242. The process of claim 207 wherein R4 is Cl.
243. The process of claim 207 wherein R2 is d-C4 alkyl.
244. The process of claim 207 wherein R2 is methyl.
245. The process of claim 207 wherein R1 is H.
246. The process of claim 207 wherein R1 is H or d-C4 alkyl, R2 is CrC4 alkyl, R3 is H, R4 is halo, R5 is H, R6 is H, R7a is H, R7b is H, R8a is H, and R8b is H.
247. The process of claim 207 wherein R1 is H, R2 is Me, R3 is H, R4 is Cl, R5 is H, R6 is H, R7a is H,
R >7'b° is H, R8a is H, and W° is H
248. A process for preparing a compound of Formula I:
I or salt form thereof, wherein: R1 is H or Ci-Cg alkyl; R2 is Ci-Cg alkyl, -CH2-0-(CrCg alkyl), C(0)O-(d-C8 allcyl), -C(0)NH-(C Cg alkyl), OH, C C4 haloalkyl, or CH2OH; R3 , R4, R5 , and R6 are each, independently, H, halo, Ci-Cg alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, C,-Cg haloalkyl, hydroxy, mercapto, OR9, SR9, alkoxyallcyl, C(0)-alkyl, C(0)0-alkyl, C(O)NH-alkyl, hydroxyalkyl, NR10Rπ, CN, NO2, heterocycloallcyl, aryl, or heteroaryl, wherein said aryl and heteroaryl can be substituted with one or more substituents selected from Cι-C8 allcyl, halo, Cι-C8 haloallcyl, and alkoxy; or R4 and R5 together with the atoms to which they are attached form a 5- or 6- member heterocyclic ring having one O atom; R7a and R7b are each, independently, H, halo, Ci-Cg alkyl, d-C8 alkenyl, C2-Cg alkynyl, C3-C7 cycloalkyl, Ci-Cg haloalkyl, alkoxyalkyl, hydroxy, C(0)-alkyl, C(0)O-alkyl, C(0)NH-alkyl, or hydroxyalkyl, or R7a and R7b together with the carbon atom to which they are attached form a C3-C7 cycloalkyl group; R8a and R8b are each, independently, H, halo, CrC8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloallcyl, C C8 haloallcyl, alkoxyallcyl, hydroxy, C(0)-alkyl, C(0)O-alkyl, C(0)NH-alkyl, or hydroxyallcyl, or R8 and R8b together with the carbon atom to which they are attached form a C3-C7 cycloallcyl group; R9 is H, Cι-C8 alkyl, CrC8 alkenyl, CrC8 alkynyl, C3-C7 cycloallcyl, C C8 haloalkyl, aralkyl, aryl, heteroaryl, heteroarylallcyl, or allyl; R10 and R11 are each, independently, H, C C8 alkyl, Cι-C8 alkenyl, Cι-C8 alkynyl, C3-C7 cycloallcyl, Cι-C8 haloallcyl, arallcyl, aryl, heteroaryl, heteroarylallcyl, or allyl, or R10 and R11 together with the N atom to which they are attached form a heterocyclic ring; comprising: (a) reacting a compound of Formula IN:
IN or salt form thereof, with a compound of Formula:
wherein: L is halo, hydroxy, Ci-Cg alkoxy, Ci-Cg thioalkoxy, Ci-Cg acyloxy, -OS02R, or
-OSi(R')3; R is Ci-Cg alkyl, aryl, or heteroaryl each optionally substituted by one or more halo, cyano, nitro, C1-C4 alkyl, C1-C4 haloallcyl, C1-C4 alkoxy, or C1-C4 haloalkoxy; R' is Cj-Cg alkyl; and Q is a leaving group, for a time and under conditions suitable for forming a compound of Formula III:
or salt form thereof; (b) reacting said compound of Formula III with a reducing agent optionally in the presence of a Lewis acid for a time and under conditions suitable for forming a compound of Formula Ilia:
Ilia and (c) reacting said compound of Formula Ilia with a cyclizing reagent for a time and under conditions suitable for forming said compound of Formula I.
249. The process of claim 248 wherein Q is Cl.
250. The process of claim 248 wherein then reacting of step (a) is carried out in the presence of base.
251. The process of claim 248 wherein said reducing agent comprises, a borane.
252. The process of claim 248 wherein said reducing agent comprises BH3.
253. The process of claim 248 wherein said reducing agent comprises a metal hydride.
254. The process of claim 248 wherein said reducing agent comprises a borohydride or aluminum hydride. ]
255. The process of claim 248 wherein said cyclizing reagent comprises a Lewis acid.
256. The process of claim 248 wherein said cyclizing reagent comprises a Ci-Cg allcyl aluminum halide.
257. The process of claim 248 wherein said cyclizing reagent comprises a C2-Ci6 dialkyl aluminum halide.
258. The process of claim 248a wherein said cyclizing reagent comprises AICI3.
259. The process of claim 248 wherein said cyclizing reagent comprises an acid.
260. The process of claim 248 wherein said cyclizing reagent comprises sulfuric acid.
261. The process of claim 248 wherein said reacting of step c) is carried out in the absence of solvent.
262. The process of claim 248 wherein said reacting of step c) is carried out in the presence of solvent.
263. The process of claim 248 wherein said reacting of step c) is carried out in a non-polar solvent.
264. The process of claim 248 wherein said reacting of step c) is carried out in a solvent comprising decahydronaphthalene or 1,2-dichlorobenzene.
265. The process of claim 248 wherein: R2 is Ci-Cg alkyl, -CH2-O-(C,-C8 alkyl), C(0)0-(d-C8 allcyl), -C(O)NH-(C C8 alkyl), OH, or CH2OH; R3 and R6 are each H; R4 and R5 are each, independently, H, halo, Ci-Cg haloallcyl, hydroxy, OR9, SR9, alkoxyalkyl, NHR10, NR10Rn, aryl, or heteroaryl, wherein said aryl can be substituted with up to two substituents selected from Cι-C8 allcyl, halo, Ci-Cg haloalkyl, and alkoxy, and said heteroaryl can be optionally substituted with up to two substituents selected from halogen and Cι-C8 alkyl; or R4 and R5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; R7a is H; R7b is H or Ci-Cg alkyl; R8 and R8b are each H; and R10 and R11 are each, independently, Ci-Cg allcyl, Ci-Cg alkenyl, Ci-Cg haloallcyl, aryl, heteroaryl, arallcyl, heteroarylallcyl, or allyl; provided that: (A) ifR2 is methyl and R4 is H, then R5 is not thiazole, substituted thiazole or a thiazole derivative; \ (B) if R7a is H and R7b is other than H, then neither R4 nor R5 can be H; (C) ifR1 and R2 are methyl, and R5 is H then R4 is not NHR10 or NR10RU; and (D) if 1 and R2 are methyl and R5 is H, then R4 is not imidazolyl, substituted imidazolyl, or an imidazole derivative.
266. The process of claim 265 wherein R1 is H.
267. The process of claim 265 wherein R1 is Ci-Cg allcyl.
268. The process of claim 265 wherein R 2 . is methyl, ethyl, n-propyl, or isopropyl
269. The process of claim 265 wherein R2 is methyl.
270. The process of claim 265 wherein R4 is Cl, Br, haloallcyl, CF3, thiophenyl, furanyl, pyrrolyl, pyrazolyl, or imidazolyl.
271. The process of claim 265 wherein R4 is Cl.
272. The process of claim 265 wherein R5 is methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, or phenyl, wherein said imidazolyl is optionally substituted by one or more halo or methyl and said phenyl is optionally substituted with up to two substituents selected from Ci-Cg alkyl, Cι-C8 haloalkyl, halo, and alkoxy.
273. The process of claim 265 wherein R5 is H.
274. The process of claim 248 wherein: R2 is Cι-C4 alkyl, -CH2-0-(Cι-C4 alkyl), C,-C4 haloalkyl, or CH2OH; R3 , R4, R5 , and R6 are each, independently, H, halo, C1-C4 alkyl, C1-C4 haloallcyl, hydroxy, NH2, CN, or NO2; and R7a ^ R7bj R8a ^ md R8b &χQ Q&άl R. provided that: (H) when R2 is CrC4 alkyl, -CH2-0-(d-C4 alkyl), or CH2OH, then R3 and R6 are not both H; and (I) when R2 is CH3, then R3, R4, and R6 are each H and R5 is not H or isopropyl.
275. The process of claim 274 wherein R1 is H.
276. The process of claim 274 wherein R1 is Cι-C8 alkyl.
277. The process of claim 274 wherein R2 is C1-C4 alkyl or C1-C4 haloallcyl.
278. The process of claim 274 wherein R2 is methyl, ethyl, isopropyl, n-butyl, or CF3.
279. The process of claim 274 wherein R3, R4, R5, and R6 are each, independently, H, methyl, NH2, CN, halo, CF3, N02, or OH.
280. The process of claim 248 wherein R7a, R7b, R8a, and R8b are each H.
281. The process of claim 248 wherein R3 and R6 are each H.
282. The process of claim 248 wherein R , R , and R are each H,
283. The process of claim 248 wherein R4 is halo.
284. The process of claim 248 wherein R is Cl.
285. The process of claim 248 wherein R2 is CrC4 alkyl.
286. The process of claim 248 wherein R2 is methyl.
287. The process of claim 248 wherein R is H.
288. The process of claim 248 wherein R1 is H or d-d allcyl, R2 is CrC4 allcyl, R3 is H, R4 is halo, R5 is H, W is H, R'a is H, R'D is H, RBa is H, and R 8δbD : is H.
289. The process of claim 248 wherein R1 is H, R2 is Me, R3 is H, R4 is Cl, R5 is H, R6 is H, R7a is H, R7b is H, R8a is H, and R8b is H.
290. A method of resolving a mixture of compounds of Formula la and lb:
la lb wherein: R1 is H or d-C8 alkyl; R2 is CrC8 allcyl, -CH2-0-(C,-C8 allcyl), C(0)O-(C C8 alkyl), -C(0)NH-(C,-C8 alkyl), OH, Cr C4 haloallcyl, or CH2OH; R3 , R4, R5 , and R6 are each, independently, H, halo, Cι-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, C C8 haloallcyl, hydroxy, mercapto, OR9, SR9, alkoxyalkyl, C(0)-alkyl, C(0)0-alkyl, C(0)NH-alkyl, hydroxyalkyl, NR10RU, CN, N02, heterocycloallcyl, aryl, or heteroaryl, wherein said aryl and heteroaryl can be substituted with one or more substituents selected from Cι-C8 allcyl, halo, Cι-C8
haloalkyl, and alkoxy; or R and R together with the atoms to which they are attached form a 5- or 6- member heterocyclic ring having one O atom; R7a and R7b are each, independently, H, halo, Cι-C8 allcyl, C2-C8 alkenyl, C2-C3 alkynyl, C3-C7 cycloallcyl, C,-C8 haloallcyl, alkoxyallcyl, hydroxy, C(O)-alkyl, C(0)O-alkyl, C(0)NH-alkyl, or hydroxyallcyl, or R7a and R7b together with the carbon atom to which they are attached form a C3-C7 cycloalkyl group; \ R8a and R8b are each, independently, H, halo, CrC8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, C C8 haloallcyl, alkoxyalkyl, hydroxy, C(0)-alkyl, C(0)O-alkyl, C(0)NH-alkyl, or hydroxyallcyl, or R8a and R8b together with the carbon atom to which they are attached form a C3-C7 cycloallcyl group; R9 is H, d-d allcyl, CrC8 alkenyl, CrC8 alkynyl, C3-C7 cycloallcyl, C C8 haloalkyl, aralkyl, aryl, heteroaryl, heteroarylallcyl, or allyl; R10 and R11 are each, independently, H, d-C8 alkyl, C C8 alkenyl, Cι-C8 alkynyl, C3-C7 cycloallcyl, Cι-C8 haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R10 and R11 together with the N atom to which they are attached form a heterocyclic ring; comprising: contacting said mixture of compounds with a chiral resolving acid to form chiral resolving acid salts of said compounds, wherein said chiral resolving acid comprises substantially one stereoisomer; and precipitating said chiral resolving acid salts of said compounds,1 wherein the resulting precipitate is enriched in the chiral resolving acid salt of one of said compounds of Formula la or lb.
291. The method of claim 290 wherein said chiral resolving acid is tartaric acid.
292. The method of claim 290 wherein said tartaric acid is L-(+)-tartaric acid.
293. The method of claim 290 wherein said precipitate is emiched in the tartaric acid salt form of said compound of Formula la or said compound of Formula lb.
294. The method of claim 290 wherein: R2 is Ci- allcyl, -CH2-0-(C,-C8 alkyl), C(0)0-(CrC8 alkyl), -C(0)NH-(C C8 allcyl), OH, or
CH2OH; R3 and R6 are each H; R4 and R5 are each, independently, H, halo, C C8 haloalkyl, hydroxy, OR9, SR9, alkoxyalkyl, NHR10, NR10Rn, aryl, or heteroaryl, wherein said aryl can be substituted with up to two substituents selected from Cι-C8 alkyl, halo, CrC8 haloallcyl, and alkoxy, and said heteroaryl can be optionally substituted with up to two substituents selected from halogen and CrC8 allcyl; or R4 and R5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; R7a is H;
R7b is H or Ci-Cg allcyl; R8a and R8b are each H; and R10 and R11 are each, independently, Cι-C8 alkyl, Cι-C8 alkenyl, CrC8 haloalkyl, aryl, heteroaryl, arallcyl, heteroarylallcyl, or allyl; provided that: (A) ifR2 is methyl and R4 is H, then R5 is not thiazole, substituted thiazole or a thiazole derivative; (B) if R7a is H and R7b is other than H, then neither R4 nor R5 can be H; (C) if R1 and R2 are methyl, and R5 is H then R4 is not NHR10 or NR' ! ; and (D) ifR1 and R2 are methyl and R5 is H, then R4 is not imidazolyl, substituted imidazolyl, or an imidazole derivative.
295. The method of claim 294 wherein R2 is methyl, ethyl, n-propyl, or isopropyl.
296. The method of claim 294 wherein R2 is methyl.
297. The method of claim 294 wherein R4 is Cl, Br, haloallcyl, CF3, thiophenyl, furanyl, pyrrolyl, pyrazolyl, or imidazolyl.
298. The method of claim 294 wherein R4 is Cl.
299. The method of claim 294 wherein R5 is methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, or phenyl, wherein said imidazolyl is optionally substituted by one or more halo or methyl and said phenyl is optionally substituted with up to two substituents selected from Cι-C8 alkyl, Ci-Cg haloalkyl, halo, and alkoxy.
300. The method of claim 294 wherein R5 is H.
301. The method of claim 290 wherein: R2 is d-d alkyl, -CH2-0-(d-C4 alkyl), d-C4 haloalkyl, or CH2OH; R3 , R4, R5 , and R6 are each, independently, H, halo, C1-C4 alkyl, d-C haloalkyl, hydroxy, NH2, CN, or N02; and R7a 5 R7bj R8a ? ^ R8b &χQ Q&ς, JJ. provided that: (TT) when R2 is CrC4 alkyl, -CH2-0-(CrC4 alkyl), or CH2OH, then R3 and R6 are not both H; and (I) when R2 is CH3, then R3, R4, and R6 are each H and R.5 is not H or isopropyl.
302. The method of claim 290 wherein R7a, R7b, R8a, and R8b are each H.
303. The method of claim 290 wherein R3 and R6 are each H.
304. The method of claim 290 wherein W, W, and W are each H
305. The method of claim 290 wherein R is halo
306. The method of claim 290 wherein R4 is Cl.
307. The method of claim 290 wherein R2 is C C4 alkyl.
308. The method of claim 290 wherein R is methyl.
309. The method of claim 290 wherein R1 is H.
310. The method of claim 290 wherein R1 is H or CrC4 allcyl, R2 is d-C4 alkyl, R3 is H, R4 is halo, R5 is H, W is H, R a is H, R/D is H, R8a is H, and W 8b" is H.
311. The method of claim 290 wherein R1 is H, R2 is Me, R3 is H, R4 is Cl, R5 is H, R6 is H, R7a is H,
R/D is H, Rδa is H, and Rδ 8bD i ;s H.
312. The method of claim 290 wherein said contacting is carried out in a solvent comprising t-butanol.
313. The method of claim 290 wherein said contacting is carried out in a solvent comprising acetone.
314. A compound of Formula II or Ilia:
II Ilia or salt form thereof, wherein: R1 is H or Ci-Cg alkyl;
R2 is d-Cg ailcyir-CH2- -(Cι-C8 alkyl), C(O)O-(C Cg allcyl), -C(O)NH-(C Cg alkyl), OH, Cr
C4 haloallcyl, or CH2OH; R3 , R4, R5 , and R6 are each, independently, H, halo, C C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, CrC8 haloallcyl, hydroxy, mercapto, OR9, SR9, alkoxyalkyl, C(0)-alkyl, C(O)0-alkyl, C(O)NH-alkyl, hydroxyalkyl, NR10Rn, CN, N02, heterocycloallcyl, aryl, or heteroaryl, wherein said aryl and heteroaryl can be substituted with one or more substituents selected from d-C8 allcyl, halo, C C8 haloallcyl, and alkoxy; or R4 and R5 together with the atoms to which they are attached form a 5- or 6- member heterocyclic ring having one O atom; R7a and R7b are each, independently, H, halo, d- alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloallcyl, C C8 haloallcyl, alkoxyallcyl, hydroxy, C(0)-allcyl, C(0)O-alkyl, C(0)NH-alkyl, or hydroxyalkyl, or R7a and R7b together with the carbon atom to which they are attached form a C3-C7 cycloalkyl group; R8a and R8b are each, independently, H, halo, Cι-C8 allcyl, C2-C8 alkenyl, C2-C8 allcynyl, C3-C7 cycloallcyl, C C8 haloalkyl, alkoxyalkyl, hydroxy, C(0)-alkyl, C(0)O-allcyl, C(0)NH-alkyl, or hydroxyallcyl, or RSa and R8b together with the carbon atom to which they are attached form a C3-C7 cycloallcyl group; R9 is H, CrCs alkyl, Cι-C8 alkenyl, d-C8 alkynyl, C3-C7 cycloallcyl, Cι-C8 haloalkyl, arallcyl, aryl, heteroaryl, heteroarylallcyl, or allyl; R10 and R11 are each, independently, H, CrC8 allcyl, Cι-C8 alkenyl, CrC8 alkynyl, C3-C7 cycloallcyl, C Cs haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R10 and Rπ together with the N atom to which they are attached form a heterocyclic ring; and L is halo, hydroxy, Cι-C8 alkoxy, Cι-C8 thioalkoxy, C]-C8 acyloxy, -OS02R, or -OSi(R')3; R is d- allcyl, aryl, or heteroaryl each optionally substituted by one or more halo, cyano, nitro, C1-C4 allcyl, C1-C4 haloallcyl, C1-C4 alkoxy, or C1-C4 haloalkoxy; and R' is Ci-d allcyl.
315. The compound of claim 314 wherein: R2 is Ci-Cg alkyl, -CH2-0-(d-C8 alkyl), C(0)O-(C C8 alkyl), -C(0)NH-(C C8 alkyl), OH, or CH2OH; R3 and R6 are each H; R4 and R5 are each, independently, H, halo, Cι-C8 haloalkyl, hydroxy, OR9, SR9, alkoxyalkyl, NHR10, NR10RU, aryl, or heteroaryl, wherein said aryl can be substituted with up to two substituents selected from Ci- alkyl, halo, CrCg haloallcyl, and alkoxy, and said heteroaryl can be optionally substituted with up to two substituents selected from halogen and CrCg alkyl; or R4 and R5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; R7a is H; R7b is H or Ci-d allcyl;
R8a and R b are each H; and R10 and Ru are each, independently, CrC8 allcyl, CrC8 alkenyl, Cι-C8 haloallcyl, aryl, heteroaryl, arallcyl, heteroarylallcyl, or allyl; provided that: (A) ifR2 is methyl and R4 is H, then R5 is not thiazole, substituted thiazole or a thiazole derivative; (B) if R7a is H and R7b is other than H, then neither R4 nor R5 can be H; (C) ifR1 and R2 are methyl, and R5 is H then R4 is not NHR10 or NR10Rπ; and (D) ifR1 and R2 are methyl and R5 is H, then R4 is not imidazolyl, substituted imidazolyl, or an imidazole derivative.
316. The compound of claim 315 wherein R2 is methyl, ethyl, n-propyl, or isopropyl.
317. The compound of claim 315 wherein R2 is methyl.
318. The compound of claim 315 wherein R4 is Cl, Br, haloallcyl, CF3, thiophenyl, furanyl, pyrrolyl, pyrazolyl, or imidazolyl.
319. The compound of claim 315 wherein R4 is Cl.
320. The compound of claim 315 wherein R5 is methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, or phenyl, wherein said imidazolyl is optionally substituted by one or more halo or methyl and said phenyl is optionally substituted with up to two substituents selected from Cι-C8 alkyl, Cι-C8 haloallcyl, halo, and alkoxy.
321. The compound of claim 315 wherein R5 is H.
322. The compound of claim 314 wherein: R2 is Cι-C4 alkyl, -CH2-O-(C1-C4 alkyl), CrC4 haloalkyl, or CH2OH; R3 , R4, R5 , and R6 are each, independently, H, halo, Ci- alkyl, C1-C4 haloallcyl, hydroxy, NH2, CN, or N02; and R7a ^ R7bs R8a ^ ^ R8b aχQ each R. provided that: (TT) when R2 is CrC4 alkyl, -CH2-0-(d-C4 alkyl), or CH2OH, then R3 and R6 are not both H; and (I) when R2 is CH3, then R3, R4, and R6 are each H and R5 is not H or isopropyl.
323. The compound of claim 322 wherein R7a, R7b, R8a, and R8b are each H.
324. The compound of claim 322 wherein R3 and R6 are each H.
325. The compound of claim 322 wherein R3, R5, and R6 are each H.
326. The compound of claim 322 wherein R4 is halo.
327. The compound of claim 322 wherein R4 is Cl.
328. The compound of claim 322 wherein R2 is d-C4 allcyl.
329. The compound of claim 322 wherein R2 is methyl.
330. The compound of claim 322 wherein R1 is H.
331. The compound of claim 314 wherein R7a, R7b, R8a, and R8b are each H.
332. The compound of claim 314 wherein R3 and R6 are each H.
333. The compound of claim 314 wherein R3, R5, and R6 are each H.
334. The compound of claim 314 wherein R4 is halo.
335. The compound of claim 314 wherein R4 is Cl.
336. The compound of claim 314 wherein R2 is d- alkyl.
337. The compound of claim 314 wherein R2 is methyl.
338. The compound of claim 314 wherein R1 is H.
339. The compound of claim 314 wherein R1 is H or Cι-C alkyl, R2 is d-C4 alkyl, R3 is H, R4 is halo, R5 is H, R6 is H, R7a is H, R7b is H, R8a is H, and R8b is H.
340. The compound of claim 314 wherein R1 is H, R2 is Me, R3 is H, R4 is Cl, R5 is H, R6 is H, R7a is H, R7b is H, R8a is H, and R8b is H.
341. A chiral resolving acid salt of a compound of Formula la or lb:
wherein: R1 is H or Ci-Cg alkyl; R2 is Ci-Cg allcyl, -CH2-0-(C C8 alkyl), C(0)O-(d-C8 allcyl), -C(O)NH-(C,-C8 alkyl), OH, C C4 haloallcyl, or CH2OH; R3 , R4, R5 , and R6 are each, independently, H, halo, Cι-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, CrC8 haloallcyl, hydroxy, mercapto, OR9, SR9, alkoxyalkyl, C(0)-alkyl, C(0)0-alkyl, C(0)NH-alkyl, hydroxyalkyl, NR10Rn, CN, N02, heterocycloallcyl, aryl, or heteroaryl, wherein said aryl and heteroaryl can be substituted with one or more substituents selected from Cι-C8 alkyl, halo, Cι-C8 haloalkyl, and alkoxy; or R4 and R5 together with the atoms to which they are attached form a 5- or 6- member heterocyclic ring having one O atom; R7a and R7b are each, independently, H, halo, Cι-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, C C8 haloallcyl, alkoxyallcyl, hydroxy, C(O)-alkyl, C(0)O-alkyl, C(0)NH-alkyl, or hydroxyallcyl, or R7a and R7b together with the carbon atom to which they are attached form a C3-C7 cycloallcyl group; R8a and R8b are each, independently, H, halo, d-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, C C8 haloalkyl, alkoxyalkyl, hydroxy, C(O)-alkyl, C(0)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, or R8a and R8b together with the carbon atom to which they are attached form a C3-C7 cycloalkyl group; R9 is H, Cι-C8 alkyl, Cι-C8 alkenyl, Ci- alkynyl, C3-C7 cycloallcyl, Cι-C8 haloalkyl, arallcyl, aryl, heteroaryl, heteroarylallcyl, or allyl; and R10 and R11 are each, independently, H, Cι-C8 alkyl, Ci-d alkenyl, Ci-Cg alkynyl, C3-C7 cycloallcyl, Cι-C8 haloallcyl, arallcyl, aryl, heteroaryl, heteroarylallcyl, or allyl, or R10 and R11 together with the N atom to which they are attached form a heterocyclic ring.
342. The salt of claim 341 wherein said salt is a tartaric acid salt.
343. The salt of claim 342 wherein said tartaric acid is L-(+)-tartaric acid.
344. The salt of claim 342 wherein said salt is a tartaric acid salt of a compound of Formula la or a compound of Formula lb.
345. The salt of claim 341 wherein: R2 is d-d allcyl, -CH2-0-(Cι-Cg alkyl), C(0)0-(C Cg allcyl), -C(0)NH-(Cι-C8 alkyl), OH, or CH2OH; R3 and R6 are each H; R4 and R5 are each, independently, H, halo, Ci-Cg haloallcyl, hydroxy, OR9, SR9, alkoxyallcyl, NHR10, NR10RU, aryl, or heteroaryl, wherein said aryl can be substituted with up to two substituents selected from Ci-Cg allcyl, halo, Ci- haloalkyl, and alkoxy, and said heteroaryl can be optionally substituted with up to two substituents selected from halogen and Ci-Cg alkyl; or R4 and R5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; R7a is H; R7b is H or Ci-Cg alkyl; RSa and R8b are each H; and R10 and R11 are each, independently, Ci-Cg allcyl, C]-C8 alkenyl, d-C8 haloalkyl, aryl, heteroaryl, arallcyl, heteroarylallcyl, or allyl; provided that: (A) ifR2 is methyl and R4 is H, then R5 is not thiazole, substituted thiazole or a thiazole derivative; (B) if R7a is H and R7b is other than H, then neither R4 nor R5 can be H; (C) if R1 and R2 are methyl, and R5 is H then R4 is not NHR10 or NR10Rn; and (D) ifR1 and R2 are methyl and R5 is H, then R4 is not imidazolyl, substituted imidazolyl, or an imidazole derivative.
345. The salt of claim 341 wherein: R2 is d-d alkyl, -CH2-0-(d-C4 alkyl), CrC4 haloallcyl, or CH2OH; R3 , R4, R5 , and R6 are each, independently, H, halo, d- alkyl, d- haloallcyl, hydroxy, NH2, CN, or N02; and R7a , R7b, R8a , and R8b are each H; provided that: (H) when R2 is CrC4 alkyl, -CH2-0-(CrC4 alkyl), or CH2OH, then R3 and R6 are not both H; and (I) when R2 is CH3, then R3, R4, and R6 are each H and R5 is not H or isopropyl.
346. The salt of claim 341 wherein R7a, R7b, R8a, and R8b are each H.
347. The salt of claim 341 wherein R3 and R6 are each H.
348. The salt of claim 341 wherein R3, R5, and R6 are each H.
349. The salt of claim 341 wherein R4 is halo.
350. The salt of claim 341 wherein R4 is Cl
351. The salt of claim 341 wherein R2 is CrC4 alkyl.
352. The salt of claim 341 wherein R2 is methyl.
353. The salt of claim 341 wherein R is H.
354. The salt of claim 341 wherein R1 is H or CrC4 alkyl, R2 is d-C4 allcyl, R3 is H, R4 is halo, R5 is
H, R6 is H, R7a is H, R7b is H, R* is H, and R 8SbD is H,
355. The salt of claim 341 wherein R1 is H, R2 is Me, R3 is H, R4 is Cl, R5 is H, R6 is H, R7a is H, R7b is
H, R8a is H, and Rδ 8bD is H,
356. A composition comprising at least one salt of claim 341.
357. The composition of claim 356 wherein said composition comprises said salt form of a compound of Formula la and said salt form of a compound of Formula lb, wherein said composition is enriched in one of either said salt form of a compound of Formula la or said salt form of a compound of Formula lb.
358. A process for preparing a compound of Formula V:
V or salt thereof, wherein: R1 is H or Ci-d alkyl;
R2 is Ci-Cg alkyl, -CH2-0-(Cι-C8 allcyl), C(0)0-(C C8 allcyl), -C(0)NH-(d-Cg allcyl), or C C4 haloallcyl; R3 , R4, R5 , and R6 are each, independently, H, halo, d-Cg alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloallcyl, C,-C8 haloallcyl, hydroxy, OR9, alkoxyalkyl, C(0)-allcyl, C(0)0-alkyl, C(0)NH-alkyl, hydroxyallcyl, NR10Rn, CN, N02, heterocycloalkyl, aryl, or heteroaryl, wherein said aryl and heteroaryl can be substituted with one or more substituents selected from Cι-C8 allcyl, halo, Ci-d haloallcyl, and alkoxy; or R4 and R5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; R8a and R8b are each, independently, H, halo, CrC8 allcyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloallcyl, C C8 haloallcyl, alkoxyallcyl, hydroxy, C(O)-alkyl, C(0)O-allcyl, C(O)NH-alkyl, or hydroxyallcyl, or R8a and Rsb together with the carbon atom to which they are attached form a C3-C7 cycloallcyl group; R9 is H, Cι-C8 alkyl, d-C8 alkenyl, CrC8 alkynyl, C3-C7 cycloalkyl, C C8 haloalkyl, aralkyl, aryl, heteroaryl, heteroarylallcyl, or allyl; and R10 and R11 are each, independently, H, d-C8 allcyl, Ci- alkenyl, d-C8 alkynyl, C3-C7 cycloallcyl, Cι-C8 haloallcyl, arallcyl, aryl, heteroaryl, heteroarylallcyl, or allyl, or R10 and R11 together with the N atom to which they are attached form a heterocyclic ring; comprising reacting a compound of Formula LX:
IX or salt thereof, wherein X2 is halo or S02R" and R" is Ci- allcyl, aryl, or heteroaryl each optionally substituted by one or more halo, cyano, nitro, C1-C4 allcyl, CrC4 haloalkyl, Cι-C alkoxy, or C1-C4 haloalkoxy, with a cyclizing reagent for a time and under conditions suitable for forming said compound of Formula V.
359. The process of claim 358 wherein said cyclizing reagent is a Lewis acid.
360. The process of claim 358 wherein said cyclizing reagent is A1C13.
361. The process of claim 358 wherein said reacting is carried out in the presence of a non-polar solvent.
362. The process of claim 358 wherein said reacting is carried out in the presence of 1,2- dichlorobenzene.
363. The process of claim 358 wherein said reacting is carried out at an elevated temperature.
364. The process of claim 358 wherein said reacting is carried out at a temperature between about 100 and about 150 °C.
365. The process of claim 358 wherein X2 is Br.
366. The process of claim 358 wherein: R2 is Ci-Cg alkyl, -CH2-0-(Cι-C8 alkyl), C(0)O-(C C8 alkyl), -C(O)NH-(d-C8 allcyl); R3 and R6 are each H; R4 and R5 are each, independently, H, halo, Ci-d haloalkyl, hydroxy, OR9, alkoxyalkyl, NHR10, NR10Rπ, aryl, or heteroaryl, wherein said aryl can be substituted with up to two substituents selected from d-d alkyl, halo, Ci-d haloalkyl, and alkoxy, and said heteroaryl can be optionally substituted with up to two substituents selected from halogen and C]-C8 alkyl; or R4 and R5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; R7a is H; R7b is H or d-d alkyl; R8a and R8b are each H; and R10 and R11 are each, independently, C C8 allcyl, d-C8 alkenyl, Cι-C8 haloallcyl, aryl, heteroaryl, arallcyl, heteroarylallcyl, or allyl; provided that: (A) ifR2 is methyl and R4 is H, then R5 is not thiazole, substituted thiazole or a thiazole derivative; (B) if R7a is H and R7b is other than H, then neither R4 nor R5 can be H; (C) ifR1 and R2 are methyl, and R5 is H then R4 is not NHR10 or NR10Rn; and (D) ifR1 and R2 are methyl and R5 is H, then R4 is not imidazolyl, substituted imidazolyl, or an imidazole derivative.
367. The process of claim 366 wherein R1 is H.
368. The process of claim 366 wherein R1 is Cι-C8 allcyl.
369. The process of claim 366 wherein R2 is methyl, ethyl, n-propyl, or isopropyl.
370. The process of claim 366 wherein R2 is methyl.
371. The process of claim 366 wherein R4 is Cl, Br, haloallcyl, CF3, thiophenyl, furanyl, pyrrolyl, pyrazolyl, or imidazolyl.
369. The process of claim 366 wherein R4 is Cl.
373. The process of claim 366 wherein R5 is methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, or phenyl, wherein said imidazolyl is optionally substituted by one or more halo or methyl and said phenyl is optionally substituted with up to two substituents selected from Cι-C8 alkyl, d-C8 haloalkyl, halo, and alkoxy.
374. The process of claim 366 wherein R5 is H.
375. The process of claim 355 wherein: R2 is Ci-d allcyl, -CH2-0-(d-C4 allcyl), or CrC4 haloalkyl; R3 , R4, R5 , and R6 are each, independently, H, halo, Ci-d alkyl, d-C4 haloallcyl, hydroxy, NH2, CN, or N02; and R7a ^ RΛ R8a ^ ^ R8b ^ βach R. provided that: (H) when R2 is C1-C4 alkyl or -CH2-0-(C,-C4 alkyl), then R3 and R6 are not both H; and (I) when R2 is CH3, then R3, R4, and R6 are each H and R5 is not H or isopropyl.
376. The process of claim 375 wherein R1 is H.
377. The process of claim 375 wherein R1 is Cι-C8 alkyl.
378. The process of claim 375 wherein R2 is d-d allcyl or C1-C4 haloalkyl.
379. The process of claim 375 wherein R2 is methyl, ethyl, isopropyl, n-butyl, or CF3.
380. The process of claim 375 wherein R3, R4, R5, and R6 are each, independently, H, methyl, NH2, CN, halo, CF3, N02, or OH.
381. The process of claim 358 wherein R7a, R7b, R8a, and R8b are each H.
382. The process of claim 358 wherein R3 and R6 are each H.
383. The process of claim 358 wherein R3, R5, and R6 are each H.
384. The process of claim 358 wherein R is halo.
385. The process of claim 358 wherein R is Cl.
386. The process of claim 358 wherein R2 is d-C alkyl.
387. The process of claim 358 wherein R2 is methyl.
388. The process of claim 358 wherein R1 is H.
389. The process of claim 358 wherein R1 is H or CrC4 alkyl, R2 is d-C4 alkyl, R3 is H, R4 is halo, R5 is H, R° is H, R ) 7aa . is H, R ,7,bD is H, Rsa is H, and W 8b° is H.
390. The process of claim 358 wherein R1 is H, R2 is Me, R3 is H, R4 is Cl, R5 is H, R6 is H, R7a is H, R7b is H, R8a is H, and R8b is H.
391. A process for preparing a compound of Formula IX:
IX or salt thereof, wherein: R1 is H or CrCg alkyl; R2 is CrCg allcyl, -CH2-0-(d-Cg allcyl), C(0)0-(CrCg alkyl), -C(0)NH-(C Cg alkyl), or C,-C4 haloallcyl; R3 , R4, R5 , and Rδ are each, independently, H, halo, Ci-Cg alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloallcyl, CrC8 haloalkyl, hydroxy, OR9, alkoxyallcyl, C(0)-alkyl, C(0)O-alkyl, C(0)NH-alkyl, hydroxyallcyl, NR10RU, CN, N02, heterocycloallcyl, aryl, or heteroaryl, wherein said aryl and heteroaryl can be substituted with one or more substituents selected from Ci- alkyl, halo, Cι-C8 haloallcyl, and alkoxy; or R4 and R5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom;
R8a and R8b are each, independently, H, halo, C C8 allcyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, C C8 haloallcyl, alkoxyallcyl, hydroxy, C(O)-alkyl, C(0)O-alkyl, C(0)NH-allcyl, or hydroxyallcyl, or R8a and R8b together with the carbon atom to which they are attached form a C3-C7 cycloallcyl group; R9 is H, Ci- alkyl, CrC8 alkenyl, CrC8 alkynyl, C3-C7 cycloalkyl, C C8 haloalkyl, aralkyl, aryl, heteroaryl, heteroarylallcyl, or allyl; R10 and Rn are each, independently, H, CrC8 alkyl, Cι-C8 alkenyl, CrC8 allcynyl, C3-C7 cycloallcyl, Cι-C8 haloallcyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R10 and R11 together with the N atom to which they are attached form a heterocyclic ring; and X2 is halo or S02R"; and R" is CrC8 alkyl, aryl, or heteroaryl each optionally substituted by one or more halo, cyano, nitro, C1-C4 alkyl, d-d haloalkyl, C1-C4 alkoxy, or Ci- haloalkoxy; comprising reacting a compound of Formula X:
X or salt thereof, with a halogenating/sulfonating reagent for a time and under conditions suitable for forming said compound of Formula XL
392. The process of claim 391 wherein said halogenating/sulfonating reagent is SOBr2 or SOCI2.
393. The process of claim 391 wherein X2 is Br.
394. The process of claim 391 wherein said reacting is carried out in the presence of solvent.
395. The process of claim 394 wherein said solvent comprises dimethylformamide or toluene.
396. The process of claim 394 wherein said solvent comprises dimethylformamide and toluene.
397. The process of claim 391 wherein said reacting is carried out at elevated temperature.
398. The process of claim 391 wherein said elevated temperature is from about -40 to about 80 °C.
I l l
399. The process of claim 391 wherein said compound of Formula XI is isolated.
400. The process of claim 391 wherein said compound of Formula XI is isolated by recrystallization from a solvent comprising water and alcohol.
401. The process of claim 391 wherein: R2 is Ci-Cg alkyl, -CH2-0-(d-C8 alkyl), C(O)O-(C C8 allcyl), or -C(0)NH-(C C8 alkyl); R3 and R6 are each H; R4 and R5 are each, independently, H, halo, d-C8 haloallcyl, hydroxy, OR9, alkoxyalkyl, NHR10, NR10RU, aryl, or heteroaryl, wherein said aryl can be substituted with up to two substituents selected from Crd alkyl, halo, Cι-C8 haloallcyl, and alkoxy, and said heteroaryl can be optionally substituted with up to two substituents selected from halogen and d-C8 alkyl; or R4 and R5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; R7a is H; R7b is H or Ci-Cg allcyl; R8a and R8b are each H; and R10 and R11 are each, independently, d-d alkyl, d- alkenyl, Ci-Cg haloallcyl, aryl, heteroaryl, arallcyl, heteroarylalkyl, or allyl; provided that: (A) ifR2 is methyl and R4 is H, then R5 is not thiazole, substituted thiazole or a thiazole derivative; (B) if R7a is H and R7b is other than H, then neither R4 nor R5 can be H; (C) ifR1 and R2 are methyl, and R5 is H then R4 is not NHR10 or NR10Rπ; and (D) ifR1 and R2 are methyl and R5 is H, then R4 is not imidazolyl, substituted imidazolyl, or an imidazole derivative.
402. The process of claim 401 wherein R1 is H.
403. The process of claim 401 wherein R1 is d-Cg alkyl.
404. The process of claim 402 wherein R2 is methyl, ethyl, n-propyl, or isopropyl.
405. The process of claim 403 wherein R2 is methyl.
406. The process of claim 404 wherein R4 is Cl, Br, haloalkyl, CF3, thiophenyl, furanyl, pyrrolyl, pyrazolyl, or imidazolyl.
407. The process of claim 401 wherein R4 is Cl.
408. The process of claim 401 wherein R5 is methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, or phenyl, wherein said imidazolyl is optionally substituted by one or more halo or methyl and said phenyl is optionally substituted with up to two substituents selected from d-d alkyl, CrCg haloallcyl, halo, and alkoxy.
409. The process of claim 401 wherein R5 is H.
410. The process of claim 391 wherein: R2 is Cι-C4 allcyl, -CH2-O-(d-C4 alkyl), or C C4 haloallcyl; R3 , R4, R5 , and R6 are each, independently, H, halo, C1-C4 allcyl, d-d haloallcyl, hydroxy, NH2, CN, or N02; and R7a ^ R7b? RSa ^ and R8b &χQ each R. provided that (H) when R I 2 is CrC4 alkyl or -CH2-0-(Cι-C4 alkyl), then R3 and R6 are not both H; and (I) when R2 is CH3, then R3, R4, and R6 are each H and R5 is not H or isopropyl.
411. The process of claim 410 wherein R1 is H.
412. The process of claim 410 wherein R1 is CrCg alkyl.
413. The process of claim 410 wherein R2 is C1-C4 allcyl or Cι-C4 haloalkyl.
414. The process of claim 410 wherein R2 is methyl, ethyl, isopropyl, n-butyl, or CF3.
415. The process of claim 410 wherein R3, R4, R5, and R6 are each, independently, H, methyl, NH2, CN, halo, CF3, N02, or OH.
416. The process of claim 391 wherein R7a, R7b, R8a, and R8b are each H.
417. The process of claim 391 wherein R3 and R6 are each H.
418. The process of claim 391 wherein R3, R5, and R6 are each H.
419. The process of claim 391 wherein R4 is halo.
420. The process of claim 391 wherein R4 is Cl.
421. The process of claim 391 wherein R is C C alkyl.
422. The process of claim 391 wherein R2 is methyl.
423. The process of claim 391 wherein R1 is H.
424. The process of claim 391 wherein R1 is H or CrC4 alkyl, R2 is d-C4 allcyl, R3 is H, R4 is halo, R5 is H, R6 is H, R7a is H, R7b is H, R8a is H, and R8b is H.
425. The process of claim 391 wherein R1 is H, R2 is Me, R3 is H, R4 is Cl, R5 is H, R6 is H, R7a is H, R7b is H, R8a is H, and R8b is H.
426. A process for preparing a compound of Formula X:
or salt thereof, wherein: R1 is H or Ci-Cg alkyl; R2 is d-d alkyl, -CH2-O-(Cι-C8 alkyl), C(0)O-(CrC8 allcyl), -C(0)NH-(CrC8 allcyl), or CrC4 haloallcyl; R3 , R4, R5 , and R6 are each, independently, H, halo, C C8 allcyl, C2-C8 alkenyl, C2-C8 allcynyl, d-d cycloallcyl, CrC8 haloallcyl, hydroxy, OR9, alkoxyallcyl, C(0)-alkyl, C(O)0-alkyl, C(0)NH-alkyl, hydroxyalkyl, NR10Rπ, CN, N02, heterocycloallcyl, aryl, or heteroaryl, wherein said aryl and heteroaryl can be substituted with one or more substituents selected from Cι-C8 allcyl, halo, Cι-C8 haloallcyl, and alkoxy; or R4 and R5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one 0 atom; R8a and R8b are each, independently, H, halo, Crd alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloallcyl, C C8 haloallcyl, alkoxyallcyl, hydroxy, C(0)-alkyl, C(0)O-alkyl, C(0)NH-alkyl, or hydroxyalkyl, or R8a and R8b together with the carbon atom to which they are attached form a C3-C7 cycloallcyl group; R9 is H, d- allcyl, C]-C8 alkenyl, Cι-C8 alkynyl, C -C7 cycloallcyl, C C8 haloalkyl, arallcyl, aryl, heteroaryl, heteroarylallcyl, or allyl; and '
R10 and R11 are each, independently, H, CrC8 allcyl, CrCg alkenyl, CrCg alkynyl, C3-d cycloalkyl, C Cg haloallcyl, arallcyl, aryl, heteroaryl, heteroarylallcyl, or allyl, or R10 and Rπ together with the N atom to which they are attached form a heterocyclic ring; comprising reacting a compound of Formula XI:
wherein X is a leaving group, with a compound of Formula:
for a time and under conditions suitable for forming said compound of Formula X.
427. The process of claim 426 wherein said reacting is carried out at elevated temperature.
428. The process of claim 427 wherein said temperature is from about 80 to about 110 °C.
429. The process of claim 427 wherein said reacting is carried out in the absence of solvent.
430. The process of claim 426 wherein: R2 is Ci-Cg alkyl, -CH2-0-(Cι-C8 allcyl), C(0)0-(CrC8 alkyl), or -C(0)NH-(CrC8 allcyl); R3 and R6 are each H; R4 and R5 are each, independently, H, halo, Cι-C8 haloallcyl, hydroxy, OR9, alkoxyallcyl, NHR10, NR10Rn, aryl, or heteroaryl, wherein said aryl can be substituted with up to two substituents selected from d-C8 alkyl, halo, Cι-C8 haloallcyl, and alkoxy, and said heteroaryl can be optionally substituted with up to two substituents selected from halogen and Ci-d allcyl; or R4 and R5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; R7a is H; R7b is H or Cι-C8 allcyl; R8a and R8b are each H; and
R10 and R11 are each, independently, CrCg alkyl, Cι-C8 alkenyl, Cι-C8 haloallcyl, aryl, heteroaryl, arallcyl, heteroarylalkyl, or allyl; provided that: (A) ifR2 is methyl and R4 is H, then R5 is not thiazole, substituted thiazole or a thiazole derivative; (B) if R7a is H and R7b is other than H, then neither R4 nor R5 can be H; (C) ifR1 and R2 are methyl, and R5 is H then R4 is not NHR10 or NRI0Rn; and (D) ifR1 and R2 are methyl and R5 is H, then R4 is not imidazolyl, substituted imidazolyl, or an imidazole derivative.
431. The process of claim 430 wherein R1 is H.
432. The process of claim 430 wherein R1 is C]-C8 allcyl.
433. The process of claim 430 wherein R2 is methyl, ethyl, n-propyl, or isopropyl.
434. The process of claim 430 wherein R2 is methyl.
435. The process of claim 430 wherein R is Cl, Br, haloalkyl, CF3, thiophenyl, furanyl, pyrrolyl, pyrazolyl, or imidazolyl.
436. The process of claim 430 wherein R4 is Cl.
437. The process of claim 430 wherein R5 is methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, or phenyl, wherein said imidazolyl is optionally substituted by one or more halo or methyl and said phenyl is optionally substituted with up to two substituents selected from Cι-C8 alkyl, Cι-C8 haloalkyl, halo, and alkoxy.
438. The process of claim 430 wherein R5 is H.
439. The process of claim 426 wherein: R2 is d-d alkyl, -CH2-0-(d-C4 alkyl), or d-d haloallcyl; R3 , R4, R5 , and R6 are each, independently, H, halo, C C4 alkyl, d-C haloallcyl, hydroxy, NH2, CN, or N02; and R7a ^ RΛ R8a ^ md RSb &χQ βach R. provided that: (H) when R2 is CrC4 alkyl or -CH2-0-(Cι-C4 allcyl), then R3 and R6 are not both H; and (I) when R2 is CH3, then R3, R4, and R6 are each H and R5 is not H or isopropyl.
440. The process of claim 439 wherein R1 is H.
441. The process of claim 439 wherein R1 is d-d allcyl.
442. The process of claim 439 wherein R2 is d-d allcyl or CrC4 haloalkyl.
443. The process of claim 439 wherein R2 is methyl, ethyl, isopropyl, n-butyl, or CF3.
444. The process of claim 439 wherein R3, R4, R5, and R6 are each, independently, H, methyl, NH2, CN, halo, CF3, N02, or OH.
445. The process of claim 426 wherein R7a, R7b, R8a, and R8b are each H.
446. The process of claim 426 wherein R3 and R6 are each H.
447. The process of claim 426 wherein R3, R5, and R6 are each H.
448. The process of claim 426 wherein R4 is halo.
449. The process of claim 426 wherein R4 is Cl.
450. The process of claim 426 wherein R2 is d-d alkyl.
451. The process of claim 426 wherein R2 is methyl.
452. The process of claim 426 wherein R1 is H.
453. The process of claim 426 wherein R1 is H or C C4 alkyl, R2 is CrC4 alkyl, R3 is H, R4 is halo, R5 is H, Rδ is H, R7a is H, R7b is H, R8a is H, and R8b is H.
454. The process of claim 426 wherein R1 is H, R' is Me, W is H, R4 is Cl, R3 is H, W is H, R a is H R7b is H, R8a is H, and R8b is H.
455. A process for preparing a compound of Formula V:
V or salt thereof, wherein: R1 is H or Ci-Cg allcyl; R2 is Ci-Cg alkyl, -CH2-0-(C C8 alkyl), C(O)O-(Cι-Cg allcyl), -C(0)NH-(CrC8 allcyl), or CrC4 haloalkyl; R3 , R4, R5 , and R6 are each, independently, H, halo, Cι-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloallcyl, C C8 haloallcyl, hydroxy, OR9, alkoxyalkyl, C(0)-alkyl, C(0)0-alkyl, C(0)NH-alkyl, hydroxyalkyl, NR10Rn, CN, NO2, heterocycloallcyl, aryl, or heteroaryl, wherein said aryl and heteroaryl can be substituted with one or more substituents selected from Cι-C8 alkyl, halo, C]-C8 haloalkyl, and alkoxy; or R4 and R5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; R8a and R8b are each, independently, H, halo, CrC8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloallcyl, C C8 haloallcyl, alkoxyalkyl, hydroxy, C(O)-alkyl, C(0)0-alkyl, C(0)NH-alkyl, or hydroxyallcyl, or R8a and RSb together with the carbon atom to which they are attached form a C3-C7 cycloallcyl group; R9 is H, Ci-d allcyl, d-d alkenyl, CrC8 alkynyl, C3-C7 cycloallcyl, C C8 haloalkyl, arallcyl, aryl, heteroaryl, heteroarylallcyl, or allyl; and R10 and Rπ are each, independently, H, CrC8 allcyl, Cι-C8 alkenyl, Cι-C8 allcynyl, C3-C7 cycloallcyl, Cι-C8 haloallcyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R10 and R11 together with the N atom to which they are attached form a heterocyclic ring; comprising: a) reacting a compound of Formula X:
X
or salt thereof; with a halogenating/sulfonating reagent for a time and under conditions suitable for forming a compound of Formula LX:
LX or salt thereof; wherein X2 is halo or S02R" and R" is CrC8 allcyl, aryl, or heteroaryl each optionally substituted by one or more halo, cyano, nitro, d-d alkyl, d- haloalkyl, Cι-C4 alkoxy, or d-d haloalkoxy; and b) reacting said compound of Formula LX with a cyclizing reagent for a time and under conditions suitable for forming said compound of Formula V.
456. The process of claim 455 wherein said cyclizing reagent is a Lewis acid.
457. The process of claim 455 wherein said cyclizing reagent is A1C13.
458. The process of claim 455 wherein said reacting of step (b) is carried out in the presence of a non- polar solvent.
459. The process of claim 455 wherein said reacting of step (b) is carried out in the presence of 1,2- dichlorobenzene.
460. The process of claim 455 wherein said reacting of step (b) is carried out at an elevated temperature. ,
461. The process of claim 455 wherein said halogenating/sulfonating reagent is SOBr2 or SOCl2.
462. The process of claim 455 wherein X2 is Br.
463. The process of claim 455 wherein said reacting of step (a) is carried out in the presence of solvent.
464. The process of claim 463 wherein said solvent comprises dimethylformamide or toluene.
465. The process of claim 463 wherein said solvent comprises dimethylformamide and toluene.
466. The process of claim 455 wherein said compound of Formula XI is isolated.
467. The process of claim 466 wherein said compound of Formula XI is isolated by recrystallization from a solvent comprising water and alcohol.
468. The process of claim 455 wherein: R2 is Ci-Cg alkyl, -CH2-0-(C,-C8 alkyl), C(0)0-(C C8 allcyl), or -C(O)NH-(C C8 allcyl); R3 and R6 are each H; R4 and R5 are each, independently, H, halo, d-C8 haloallcyl, hydroxy, OR9, alkoxyallcyl, NHR10, NR10Rπ, aryl, or heteroaryl, wherein said aryl can be substituted with up to two substituents selected from Ci-d alkyl, halo, Cι-C8 haloallcyl, and alkoxy, and said heteroaryl can be optionally substituted with up to two substituents selected from halogen and Cι-C8 alkyl; or R4 and R5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; R7a is H; R7b is H or Ci-d alkyl; R8a and R8b are each H; and R10 and R11 are each, independently, Cι-C8 allcyl, Cι-C8 alkenyl, d-Cg haloallcyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, or allyl; provided that: (A) if R2 is methyl and R4 is H, then R5 is not thiazole, substituted thiazole or a thiazole derivative; (B) if R7a is H and R7b is other than H, then neither R4 nor R5 can be H; (C) ifR1 and R2 are methyl, and R5 is H then R4 is not NHR10 or NR10Rn; and (D) ifR1 and R2 are methyl and R5 is H, then R4 is not imidazolyl, substituted imidazolyl, or an imidazole derivative.
469. The process of claim 468 wherein R1 is H.
470. The process of claim 468 wherein R1 is C Cg alkyl.
471. The process of claim 468 wherein R2 is methyl, ethyl, n-propyl, or isopropyl.
472. The process of claim 468 wherein R2 is methyl.
473. The process of claim 468 wherein R4 is Cl, Br, haloalkyl, CF3, thiophenyl, furanyl, pyrrolyl, pyrazolyl, or imidazolyl.
474. The process of claim 468 wherein R4 is Cl.
475. The process of claim 468 wherein R ,5 is methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, or phenyl, wherein said imidazolyl is optionally substituted by one or more halo or methyl and said phenyl is optionally substituted with up to two substituents selected from Ci-Cg allcyl, Ci-Cg haloalkyl, halo, and alkoxy.
476. The process of claim 468 wherein R5 is H.
477. The process of claim 455 wherein: R2 is Cι-C4 alkyl, -CH2-0-(d-C4 alkyl), or C C4 haloallcyl; R3 , R4, R5 , and Rδ are each, independently, H, halo, Ci-d allcyl, C]-C haloalkyl, hydroxy, NH2, CN, orN02; and R7a ^ RΛ R8a ^ md R8b & Q each JJ. provided that: (H) when R2 is C C4 alkyl or -CH2-0-(Cι-C4 alkyl), then R3 and R6 are not both H; and (I) when R2 is CH3, then R3, R4, and R6 are each H and R5 is not H or isopropyl.
478. The process of claim 477 wherein R1 is H.
479. The process of claim 477 wherein R1 is C Cg allcyl.
480. The process of claim 477 wherein R2 is C C4 allcyl or Cι-C4 haloallcyl.
481. The process of claim 477 wherein R2 is methyl, ethyl, isopropyl, n-butyl, or CF3.
482. The process of claim 477 wherein R3, R4, W, and R6 are each, independently, H, methyl, NH2, CN, halo, CF3, N02, or OH.
483. The process of claim 455 wherein R7a, R7b, R8a, and R8b are each H.
484. The process of claim 455 wherein R3 and R6 are each H.
485. The process of claim 455 wherein R3, R5, and R6 are each H.
486. The process of claim 455 wherein R is halo.
487. The process of claim 455 wherein R is Cl.
488. The process of claim 455 wherein R is Cι-C alkyl.
489. The process of claim 455 wherein R2 is methyl.
490. The process of claim 455 wherein R1 is H.
491. The process of claim 455 wherein R1 is H or Ci-d alkyl, R2 is Ci-d alkyl, R3 is H, R4 is halo, R5 is H, W is H, R'a is H, R/D is H, Rsa is H, and R 8SbD is H
492. The process of claim 455 wherein R1 is H, R2 is Me, R3 is H, R4 is Cl, R5 is H, R6 is H, R7a is H,
R ,7/bD i •s H, R8a is H, and R8D is H,
493. A process for preparing a compound of Formula V:
or salt thereof, wherein: R1 is H or Ci-Cg alkyl; R2 is Ci-Cg alkyl, -CH2-O-(Cι-Cg alkyl), C(O)O-(d-C8 alkyl), -C(0)NH-(CrC8 alkyl), or CrC4 haloalkyl; R3 , R4, R5 , and R6 are each, independently, H, halo, Ci-d allcyl, C2-C8 alkenyl, C2-C8 alkynyl, d-d cycloallcyl, C C8 haloallcyl, hydroxy, OR9, alkoxyalkyl, C(0)-alkyl, C(0)0-alkyl, C(O)NH-alkyl, hydroxyalkyl, NR10Rn, CN, N02, heterocycloalkyl, aryl, or heteroaryl, wherein said aryl and heteroaryl can be substituted with one or more substituents selected from Ci-Cg alkyl, halo, Ci-Cg haloalkyl, and alkoxy; or R4 and R5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; R8a and R8b are each, independently, H, halo, Ci-Cg alkyl, C2-Cg alkenyl, C2-C3 alkynyl, C3-C7 cycloallcyl, Ci- haloallcyl, alkoxyallcyl, hydroxy, C(0)-alkyl, C(0)O-alkyl, C(0)NH-alkyl, or
hydroxyalkyl, or RSa and R8b together with the carbon atom to which they are attached form a C3-C7 cycloalkyl group; R9 is H, Ci-Cg alkyl, CrCg alkenyl, CrC8 alkynyl, C3-C7 cycloallcyl, CrC8 haloallcyl, arallcyl, aryl, heteroaryl, heteroarylallcyl, or allyl; and R10 and R11 are each, independently, H, d-d alkyl, Cι-C8 alkenyl, Ci-Cg alkynyl, C3-C7 cycloallcyl, Cj-Cg haloallcyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R10 and R11 together with the N atom to which they are attached form a heterocyclic ring; comprising: a) reacting a compound of Formula XI:
wherein X is a leaving group, with a compound of Formula:
or salt thereof, for a time and under conditions suitable for forming a compound of Formula X:
X or salt thereof; b) reacting said compound of Formula X with a halogenating/sulfonating reagent for a time and under conditions suitable for forming a compound of Formula LX:
LX or salt thereof; wherein X2 is halo or S02R" and R" is d-C8 alkyl, aryl, or heteroaryl each optionally substituted by one or more halo, cyano, nitro, C C4 alkyl, d-d haloalkyl, Cι-C4 alkoxy, or Cι-C4 haloalkoxy; and c) reacting said compound of Formula LX with a cyclizing reagent for a time and under conditions suitable for forming said compound of Formula V.
494. The process of claim 493 wherein said cyclizing reagent is a Lewis acid.
495. The process of claim 493 wherein said cyclizing reagent is A1C13.
496. The process of claim 493 wherein said halogenating/sulfonating reagent is SOBr2 or SOCl2.
497. The process of claim 493 wherein X2 is Br.
498. The process of claim 493 wherein: R2 is Ci-d allcyl, -CH2-O-(C C8 alkyl), C(0)O-(d-C8 alkyl), or -C(0)NH-(CrC8 allcyl); R3 and R6 are each H; R4 and R5 are each, independently, H, halo, Ci-d haloalkyl, hydroxy, OR9, alkoxyalkyl, NHR10, NR10Rn, aryl, or heteroaryl, wherein said aryl can be substituted with up to two substituents selected from Ci- allcyl, halo, d-C8 haloallcyl, and alkoxy, and said heteroaryl can be optionally substituted with up to two substituents selected from halogen and Cι-C8 alkyl; or R4 and R5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; R7a is H; R7b is H or Ci-Cg alkyl; R8a and R8b are each H; and R10 and R11 are each, independently, Cι-C8 alkyl, Cι-C8 alkenyl, Ci- haloalkyl, aryl, heteroaryl, arallcyl, heteroarylalkyl, or allyl; provided that: (A) ifR2 is methyl and R4 is H, then R5 is not thiazole, substituted thiazole or a thiazole derivative;
.,.„ .. (B) if R7a is H and R7b is other than H, then neither R4 nor R5 can be H; (C) ifR1 and R2 are methyl, and R5 is H then R4 is not NHR10 or NR10Rn; and (D) ifR1 and R2 are methyl and R5 is H, then R4 is not imidazolyl, substituted imidazolyl, or an imidazole derivative.
499. The process of claim 498 wherein R1 is H.
500. The process of claim 498 wherein R1 is d-C8 allcyl.
501. The process of claim 498 wherein R2 is methyl, ethyl, n-propyl, or isopropyl.
502. The process of claim 498 wherein R2 is methyl.
503. The process of claim 498 wherein R4 is Cl, Br, haloalkyl, CF3, thiophenyl, furanyl, pyrrolyl, pyrazolyl, or imidazolyl.
504. The process of claim 498 wherein R4 is Cl.
505. The process of claim 498 wherein R5 is methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, or phenyl, wherein said imidazolyl is optionally substituted by one or more halo or methyl and said phenyl is optionally substituted with up to two substituents selected from Cι-C8 alkyl, Cι-C8 haloalkyl, halo, and alkoxy.
506. The process of claim 498 wherein R5 is H.
507. The process of claim 493 wherein: R2 is Ci-d alkyl, -CH2-0-(CrC4 alkyl), or Ci-d haloallcyl; R3 , R4, R5 , and R6 are each, independently, H, halo, Cι-C alkyl, Cι-C4 haloallcyl, hydroxy, NH2,
CN, or N02; and R7a ^ R7bj RSa ^ an(j R8b &χQ Q&( JJ. provided that: (TT) when R2 is CrC4 alkyl or -CH2-0-(C C4 alkyl), then R3 and R6 are not both H; and (I) when R2 is CH3, then R3, R4, and R6 are each H and R5 is not H or isopropyl.
508. The process of claim 507 wherein R1 is H.
509. The process of claim 507 wherein R1 is d-C8 alkyl.
510. The process of claim 507 wherein R2 is Cι-C4 allcyl or C C4 haloalkyl.
511. The process of claim 507 wherein R2 is methyl, ethyl, isopropyl, n-butyl, or CF3.
512. The process of claim 507 wherein R3, R4, R5, and R6 are each, independently, H, methyl, NH2, CN, halo, CF3, N02, or OH.
513. The process of claim 493 wherein R , R , Wa, and R*D are each H
514. The process of claim 493 wherein R and R are each H.
515. The process of claim 493 wherein R , R , and R are each H,
516. The process of claim 498 wherein R4 is halo.
517. The process of claim 493 wherein R4 is Cl.
518. The process of claim 493 wherein R2 is d-d alkyl.
519. The process of claim 493 wherein R2 is methyl.
520. The process of claim 493 wherein R1 is H.
521. The process of claim 493 wherein R1 is H or CrC4 allcyl, R2 is CrC4 alkyl, R3 is H, R4 is halo, R5 is H, R6 is H, R7a is H, R7b is H, R8a is H, and R8b is H.
522. The process of claim 493 wherein R1 is H, R2 is Me, W is H, R4 is Cl, R5 is H, R6 is H, R7a is H,
R >7bD . is H, R >88aa is H, and R 88bD is H
523. A process for preparing a compound of Formula V:
V
or salt thereof, wherein: R1 is H or Ci-Cg alkyl; R2 is d-Cg alkyl, -CH2-0-(C,-Cg alkyl), C(0)0-(d-Cg alkyl), -C(0)NH-(d-C8 alkyl), or CrC4 haloalkyl; R3 , R4, R5 , and R6 are each, independently, H, halo, C C8 allcyl, C2-C8 alkenyl, C2-C8 allcynyl, C3-C7 cycloalkyl, Ci-Cg haloalkyl, hydroxy, OR9, alkoxyalkyl, C(0)-alkyl, C(O)0-alkyl, C(O)NH-alkyl, hydroxyalkyl, NR10Rn, CN, N02, heterocycloallcyl, aryl, or heteroaryl, wherein said aryl and heteroaryl can be substituted with one or more substituents selected from d-d alkyl, halo, Cι-C8 haloallcyl, and alkoxy; or R4 and R5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; RSa and R8b are each, independently, H, halo, C C8 allcyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloallcyl, CrC8 haloallcyl, alkoxyallcyl, hydroxy, C(0)-alkyl, C(0)0-alkyl, C(0)NH-alkyl, or hydroxyallcyl, or R8a and R8b together with the carbon atom to which they are attached form a C3-C7 cycloallcyl group; R9 is H, d-d alkyl, C C8 alkenyl, d-d alkynyl, C3-C7 cycloallcyl, C C8 haloalkyl, aralkyl, aryl, heteroaryl, heteroarylallcyl, or allyl; and R10 and R11 are each, independently, H, d-C8 allcyl, Cι-C8 alkenyl, d-C8 allcynyl, C3-C7 cycloalkyl, Cι-C8 haloallcyl, arallcyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R10 and R11 together with the N atom to which they are attached form a heterocyclic ring; comprising: a) reacting a compound of Foπnula XII:
XII with a halogenating/sulfonating reagent for a time and under conditions suitable for forming a compound of Formula XI:
XI wherein X1 is a leaving group; b) reacting said compound of Formula XI with a compound of Formula:
or salt thereof, for a time and under conditions suitable for forming a compound of Formula X:
X or salt thereof; c) reacting said compound of Formula X with a further halogenating/sulfonating reagent for a time and under conditions suitable for forming a compound of Formula IX:
LX or salt thereof; wherein X2 is halo or SO2R" and R" is Ci-d alkyl, aryl, or heteroaryl each optionally substituted by one or more halo, cyano, nitro, d-d allcyl, C1-C4 haloalkyl, d-d alkoxy, or C1-C4 haloalkoxy; and d) reacting said compound of Formula IX with a cyclizing reagent for a time and under conditions suitable for forming said compound of Formula V.
524. The process of claim 523 wherein said cyclizing reagent is a Lewis acid.
525. The process of claim 524 wherein said cyclizing reagent is AICI3.
526. The process of claim 523 wherein said halogenating/sulfonating reagent is PBr3 or PCI3.
527. The process of claim 523 wherein said further halogenating/sulfonating reagent is SOBr2 or
SOC1-
528. The process of claim 523 wherein X2 is Br.
529. The process of claim 523 wherein X is Br.
530. The process of claim 523 wherein: R2 is Ci-Cg alkyl, -CH2-0-(C,-C8 alkyl), C(O)O-(C C8 allcyl), or -C(0)NH-(C C8 allcyl); R3 and R6 are each H; R4 and R5 are each, independently, H, halo, Cι-C8 haloallcyl, hydroxy, OR9, alkoxyallcyl, NHR10, NRI0Rn, aryl, or heteroaryl, wherein said aryl can be substituted with up to two substituents selected from d-d alkyl, halo, Ci-Cg haloallcyl, and alkoxy, and said heteroaryl can be optionally substituted with up to two substituents selected from halogen and Cι-C8 allcyl; or R4 and R5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; R7a is H; R7b is H or Ci-Cg allcyl; R8a and R8b are each H; and R10 and R11 are each, independently, Cι-C8 allcyl, Ci-Cg alkenyl, Cι-C8 haloallcyl, aryl, heteroaryl, arallcyl, heteroarylalkyl, or allyl; provided that: (A) ifR2 is methyl and R4 is H, then R5 is not thiazole, substituted thiazole or a thiazole derivative; (B) if R7a is H and R7b is other than H, then neither R4 nor R5 can be H; (C) ifR1 and R2 are methyl, and R5 is H then R4 is not NHR10 or NR10RU; and (D) if R1 and R2 are methyl and R5 is H, then R4 is not imidazolyl, substituted imidazolyl, or an imidazole derivative.
531. The process of claim 530 wherein R1 is H.
532. The process of claim 530 wherein R1 is Cι-C8 alkyl.
533. The process of claim 530 wherein R2 is methyl, ethyl, n-propyl, or isopropyl.
534. The process of claim 530 wherein R2 is methyl.
535. The process of claim 530 wherein R4 is Cl, Br, haloallcyl, CF3, thiophenyl, furanyl, pyrrolyl, pyrazolyl, or imidazolyl.
536. The process of claim 530 wherein R4 is Cl.
537. The process of claim 530 wherein R5 is methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, or phenyl, wherein said imidazolyl is optionally substituted by one or more halo or methyl and said phenyl is optionally substituted with up to two substituents selected from Cι-C8 alkyl, Ci-Cg haloallcyl, halo, and alkoxy.
538. The process of claim 530 wherein R5 is H.
539. The process of claim 523 wherein: R2 is Ci- alkyl, -CH2-O-(d-C4 alkyl), or CrC4 haloalkyl; R3 , R4, R5 , and R6 are each, independently, H, halo, d-C allcyl, Ci- haloallcyl, hydroxy, NH2,
CN, orN02; and RR ,77'aaa ,, RR ,77/bbD,, R8a , and R 88bD a . re each H; provided that: ((HH)) wwhheenn R2 is CrC4 allcyl or -CH2-0-(C C4 alkyl), then R3 and R6 are not both H; and (I) when W is CH3, then RJ, R4, and R° are each H and R3 is not H or isopropyl.
540. The process of claim 539 wherein R1 is H.
541. The process of claim 539 wherein R1 is Ci-Cg alkyl.
542. The process of claim 539 wherein R2 is Cι-C4 alkyl or C1-C4 haloallcyl.
543. The process of claim 539 wherein R2 is methyl, ethyl, isopropyl, n-butyl, or CF .
544. The process of claim 539 wherein R3, R4, R5, and R6 are each, independently, H, methyl, NH2, CN, halo, CF3, NO2, or OH.
545. The process of claim 523 wherein R7a, R7b, R8a, and R8b are each H.
546. The process of claim 523 wherein R3 and R6 are each H.
547. The process of claim 523 wherein R3, R5, and R6 are each H.
548. The process of claim 523 wherein R4 is halo.
549. The process of claim 523 wherein R is Cl.
560. The process of claim 523 wherein R2 is CrC allcyl.
561. The process of claim 523 wherein R2 is methyl.
562. The process of claim 523 wherein R1 is H.
563. The process of claim 523 wherein R1 is H or CrC4 alkyl, R2 is Cι-C4 allcyl, R3 is H, R4 is halo, R5 is H, R6 is H, R7a is H, R7b is H, R8a is H, and R8b is H.
564. The process of claim 523 wherein R1 is H, R2 is Me, R3 is H, R4 is Cl, R5 is H, R6 is H, R7a is H,
R >7'b° i •s T Hj, r R> 88aa is H, and W 8b° is H,
565. A compound of Formula LX or X:
IX X or salt form thereof, wherein: R1 is H or Ci-Cg allcyl; R2 is d-Cg alkyl, -CH2-0-(CrCg alkyl), C(O)0-(C Cg alkyl), -C(0)NH-(d-Cg alkyl), or C C4 haloalkyl; R3 , R4, R5 , and R6 are each, independently, H, halo, Ci-d alkyl, C2-C8 alkenyl, C2-C8 alkynyl, d-d cycloallcyl, C,-C8 haloallcyl, hydroxy, OR9, alkoxyalkyl, C(0)-alkyl, C(0)0-alkyl, C(O)NH-alkyl, hydroxyallcyl, NR10Rπ, CN, N02, heterocycloalkyl, aryl, or heteroaryl, wherein said aryl and heteroaryl can be substituted with one or more substituents selected from Cι-C8 allcyl, halo, Cι-C8 haloalkyl, and alkoxy; or R4 and R5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; R8a and R8b are each, independently, H, halo, CrC8 allcyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, C,-C8 haloallcyl, alkoxyallcyl, hydroxy, C(O)-alkyl, C(0)O-alkyl, C(0)NH-alkyl, or hydroxyallcyl, or R8a and R8b together with the carbon atom to which they are attached form a C3-C7 cycloallcyl group;
n iι ,, R9 is H, Ci-d allcyl, CrC8 alkenyl, d-C8 alkynyl, C3-C7 cycloallcyl, C C8 haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl; R10 and R11 are each, independently, H, Cι-C8 alkyl, C C8 alkenyl, CrC8 alkynyl, C3-C7 cycloalkyl, Cι-C8 haloalkyl, aralkyl, aryl, heteroaryl, heteroarylallcyl, or allyl, or R10 and Rπ together with the N atom to which they are attached form a heterocyclic ring; X2 is halo or S02R"; and R" is Ci-d alkyl, aryl, or heteroaryl each optionally substituted by one or more halo, cyano, nitro, Ci-d alkyl, C C4 haloallcyl, Cι-C4 alkoxy, or C C4 haloalkoxy.
566. The compound of claim 565 wherein X2 is Br.
567. The compound of claim 565 wherein: R2 is Ci-d alkyl, -CH2-0-(d-C8 alkyl), C(0)O-(CrC8 alkyl), or -C(0)NH-(C C8 alkyl); R3 and R6 are each H; R4 and R5 are each, independently, H, halo, C C8 haloalkyl, hydroxy, OR9, alkoxyallcyl, NHR10, NR10Rn, aryl, or heteroaryl, wherein said aryl can be substituted with up to two substituents selected from C]-C8 allcyl, halo, Cι-C8 haloalkyl, and alkoxy, and said heteroaryl can be optionally substituted with up to two substituents selected from halogen and Cι-C8 alkyl; or R4 and R5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; R7a is H; R7b is H or Ci-Cg alkyl; R8a and R8b are each H; and R10 and R11 are each, independently, Cι-C8 alkyl, d-d alkenyl, Cι-C8 haloallcyl, aryl, heteroaryl, arallcyl, heteroarylalkyl, or allyl; provided that: (A) ifR2 is methyl and R4 is H, then R5 is not thiazole, substituted thiazole or a thiazole derivative; (B) if R7a is H and R7b is other than H, then neither R4 nor R5 can be H; (C) ifR1 and R2 are methyl, and R5 is H then R4 is not NHR10 or NR10Rπ; and (D) if R1 and R2 are methyl and R5 is H, then R4 is not imidazolyl, substituted imidazolyl, or an imidazole derivative.
568. The compound of claim 567 wherein R1 is H. λ
569. The compound of claim 567 wherein R1 is Cι-C8 alkyl.
570. The compound of claim 567 wherein R2 is methyl, ethyl, n-propyl, or isopropyl.
571. The compound of claim 567 wherein R2 is methyl.
572. The compound of claim 567 wherein R4 is Cl, Br, haloallcyl, CF3, thiophenyl, furanyl, pyrrolyl, pyrazolyl, or imidazolyl.
573. The compound of claim 567 wherein R4 is Cl.
574. The compound of claim 567 wherein R5 is methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, or phenyl, wherein said imidazolyl is optionally substituted by one or more halo or methyl and said phenyl is optionally substituted with up to two substituents selected from Ci-Cg alkyl, Cι-C8 haloalkyl, halo, and alkoxy.
575. The compound of claim 567 wherein R5 is H.
576. The compound of claim 567 wherein: R2 is C1-C4 allcyl, -CH2-O-(d-C4 alkyl), or Ci- haloallcyl; R3 , R4, R5 , and R6 are each, independently, H, halo, C1-C4 alkyl, d-d haloalkyl, hydroxy, NH2, CN, or N02; and R7a ^ R7bj R8a ^ and R8b & Q Q&Q jr. provided that: (TT) when R2 is C C4 alkyl or -CH2-O-(C C4 allcyl), then R3 and R6 are not both H; and (I) when R2 is CH , then R3, R4, and R6 are each H and R5 is not H or isopropyl.
577. The compound of claim 576 wherein R1 is H.
578. The compound of claim 576 wherein R1 is Cι-C8 alkyl.
579. The compound of claim 576 wherein R2 is d-d alkyl or Cι-C4 haloalkyl.
580. The compound of claim 576 wherein R2 is methyl, ethyl, isopropyl, n-butyl, or CF3.
581. The compound of claim 576 wherein R3, R4, R5, and R6 are each, independently, H, methyl, NH2, CN, halo, CF3, N02, or OH.
582. The compound of claim 567 wherein R7a, R7b, R8a, and R8b are each H.
583. The compound of claim 567 wherein R3 and R6 are each H.
584. The compound of claim 567 wherein R , R , and R are each H,
585. The compound of claim 567 wherein R4 is halo.
586. The compound of claim 567 wherein R4 is Cl.
587. The compound of claim 567 wherein R is Ci- allcyl
588. The compound of claim 567 wherein R2 is methyl.
589. The compound of claim 567 wherein R1 is H.
590. The compound of claim 567 wherein R1 is H or d-d alkyl, R is Ci- allcyl, R3 is H, R4 is halo,
R3 is H, W is H, R a is H, R/ is H, R8a is H, and W 8bϋ is H,
591. The compound of claim 567 wherein R1 is H, R2 is Me, R3 is H, R4 is Cl, R5 is H, R6 is H, R7a is
H, R7b is H, R8a is H, and R8b is H.
592. A method of resolving a mixture of compounds of Formula Va and Vb:
Va Vb
wherein: R1 is H or Ci-Cg alkyl; R2 is Ci-Cg alkyl, -CH2-0-(C C8 alkyl), C(0)0-(C C8 allcyl), -C(0)NH-(C C8 alkyl), OH, C C4 haloallcyl, or CH2OH; R3 , R4, R5 , and R6 are each, independently, H, halo, Cι-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, d-d cycloallcyl, Ci-Cg haloallcyl, hydroxy, OR9, alkoxyalkyl, C(O)-alkyl, C(0)0-alkyl, C(0)NH-alkyl, hydroxyallcyl, NR10Rπ, CN, N02, heterocycloalkyl, aryl, or heteroaryl, wherein said aryl and heteroaryl can be substituted with one or more substituents selected from Ci-Cg alkyl, halo, C C8 haloalkyl, and
alkoxy; or R4 and R5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; R8a and R8b are each, independently, H, halo, CrC8 allcyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloallcyl, C C8 haloallcyl, alkoxyalkyl, hydroxy, C(0)-alkyl, C(0)O-alkyl, C(0)NH-alkyl, or hydroxyallcyl, or R8a and R8 together with the carbon atom to which they are attached form a C3-C7 cycloalkyl group; R9 is H, Ci-d alkyl, C C8 alkenyl, CrC8 allcynyl, C3-C7 cycloalkyl, C C8 haloallcyl, aralkyl, aryl, heteroaryl, heteroarylallcyl, or allyl; and R10 and Rn are each, independently, H, C C8 allcyl, Ci-d alkenyl, C C8 alkynyl, C3-C7 cycloallcyl, Cι-C8 haloallcyl, aralkyl, aryl, heteroaryl, heteroarylallcyl, or allyl, or R10 and Ru together with the N atom to which they are attached form a heterocyclic ring; comprising: contacting said mixture of compounds with a chiral resolving acid to form chiral resolving acid salts of said compounds, wherein said chiral resolving acid comprises substantially one stereoisomer; and precipitating said chiral resolving acid salts of said compounds, wherein the resulting precipitate is enriched in the chiral resolving acid salt of one of said compounds of Formula Va or Vb.
593. The method of claim 592 wherein said chiral resolving acid is tartaric acid.
594. The method of claim 592 wherein said chiral resolving acid is L-(+)-tartaric acid.
595. The method of claim 592 wherein said precipitate is enriched in the chiral resolving acid salt of said compound of Formula Va.
596. The method of claim 592 wherein: R2 is Ci-Cg allcyl, -CH2-0-(d-C8 alkyl), C(0)0-(C,-C8 allcyl), -C(0)NH-(CrC8 alkyl), OH, or CH2OH; R3 and R6 are each H; R4 and R5 are each, independently, H, halo, Cι-C8 haloallcyl, hydroxy, OR9, alkoxyalkyl, NHR10, NR10Rπ, aryl, or heteroaryl, wherein said aryl can be substituted with up to two substituents selected from Ci-d alkyl, halo, Ci-Cg haloallcyl, and alkoxy, and said heteroaryl can be optionally substituted with up to two substituents selected from halogen and Cι-C8 alkyl; or R4 and R5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; R7a is H; R7b is H or Ci-d allcyl; R8a and R8b are each H; and R10 and R11 are each, independently, Cι-C8 allcyl, Cι-C8 alkenyl, Cι-C8 haloalkyl, aryl, heteroaryl, arallcyl, heteroarylalkyl, or allyl;
provided that: (A) ifR2 is methyl and R4 is H, then R5 is not thiazole, substituted thiazole or a thiazole derivative; (B) if R7a is H and R7b is other than H, then neither R4 nor R5 can be H; (C) ifR1 and R2 are methyl, and R5 is H then R4 is not NHR10 or NR10Rπ; and (D) ifR1 and R2 are methyl and R5 is H, then R4 is not imidazolyl, substituted imidazolyl, or an imidazole derivative.
597. The method of claim 596 wherein R1 is H.
598. The method of claim 596 wherein R1 is CrC8 alkyl.
599. The method of claim 596 wherein R2 is methyl, ethyl, n-propyl, or isopropyl.
600. The method of claim 596 wherein R is methyl.
601. The method of claim 596 wherein R4 is Cl, Br, haloallcyl, CF3, thiophenyl, furanyl, pyrrolyl, pyrazolyl, or imidazolyl.
602. The method of claim 596 wherein R4 is Cl.
603. The method of claim 596 wherein R5 is methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, or phenyl, wherein said imidazolyl is optionally substituted by one or more halo or methyl and said phenyl is optionally substituted with up to two substituents selected from Cι-C8 alkyl, Cι-C8 haloallcyl, halo, and alkoxy.
604. The method of claim 596 wherein R5 is H.
605. The method of claim 592 wherein: R2 is Cι-C4 alkyl, -CH2-0-(d-C4 alkyl), CrC4 haloallcyl, or CH2OH; R3 , R4, R5 , and R6 are each, independently, H, halo, C1-C4 alkyl, C1-C4 haloallcyl, hydroxy, NH2, CN, or N02; and R7a ^ R7b; R8a ^ and R8b &χQ Q&t jr. provided that: (TT) when R2 is CrC4 allcyl or -CH2-0-(Cι-C4 alkyl), then R3 and R6 are not both H; and (I) when R2 is CH3, then R3, R4, and R6 are each H and R5 is not H or isopropyl.
606. The method of claim 605 wherein R1 is H.
607. The method of claim 605 wherein R1 is CrC8 allcyl.
608. The method of claim 605 wherein R2 is d-d allcyl or CrC4 haloallcyl.
609. The method of claim 605 wherein R2 is methyl, ethyl, isopropyl, n-butyl, or CF3.
610. The method of claim 605 wherein R3, R4, R5, and R6 are each, independently, H, methyl, NH2, CN, halo, CF3, N02, or OH.
611. The method of claim 592 wherein R7a, R7b, R8a, and R8b are each H.
612. The method of claim 592 wherein R3 and R6 are each H.
613. The method of claim 592 wherein R , R , and R are each H.
614. The method of claim 592 wherein R4 is halo.
615. The method of claim 592 wherein R4 is Cl.
616. The method of claim 592 wherein R2 is Ci-d allcyl.
617. The method of claim 592 wherein R2 is methyl.
618. The method of claim 592 wherein R is H.
619. The method of claim 592 wherein R1 is H or CrC4 allcyl, R2 is C C4 allcyl, R3 is H, R4 is halo, R5 is H, R6 is H, R7a is H, R7b is H, R8a is H, and R8b is H.
620. The method of claim 592 wherein R1 is H, R2 is Me, R3 is H, R4 is Cl, R5 is H, R6 is H, R7a is H, R7b is H, R8a is H, and R8b is H.
621. A chiral resolving acid salt of a compound of Formula Va or Vb:
Va Vb wherein: R1 is H or Cι-C8 alkyl; R2 is Cι-C8 alkyl, -CH2-0-(Cι-C8 allcyl), C(0)O-(Cι-C8 allcyl), -C(0)NH-(C C8 alkyl), OH, d- C4 haloallcyl, or CH2OH; R3 , R4, R5 , and R6 are each, independently, H, halo, Ci- alkyl, C2-C8 alkenyl, C2-C8 allcynyl, C3-C7 cycloalkyl, CrC8 haloallcyl, hydroxy, OR9, alkoxyalkyl, C(0)-alkyl, C(0)O-alkyl, C(0)NH-alkyl, hydroxyallcyl, NR10Rπ, CN, N02, heterocycloalkyl, aryl, or heteroaryl, wherein said aryl and heteroaryl can be substituted with one or more substituents selected from Cι-C8 allcyl, halo, Cι-C8 haloallcyl, and alkoxy; or R4 and R5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; R8a and R8b are each, independently, H, halo, Ci-Cg alkyl, C2-C8 alkenyl, C2-Cg alkynyl, C3-C7 cycloalkyl, C C8 haloallcyl, alkoxyallcyl, hydroxy, C(0)-alkyl, C(0)0-allcyl, C(0)NH-alkyl, or hydroxyalkyl, or R8a and R8b together with the carbon atom to which they are attached form a C3-C7 cycloallcyl group; R9 is H, Ci-Cg allcyl, CrCg alkenyl, Ci-Cg alkynyl, C3-C7 cycloalkyl, Ci-Cg haloalkyl, aralkyl, aryl, heteroaryl, heteroarylallcyl, or allyl; and R10 and Rπ are each, independently, H, Ci-d allcyl, Ci-d alkenyl, Ci-Cg allcynyl, C3-C7 cycloalkyl, Ci-Cg haloallcyl, arallcyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R10 and R11 together with the N atom to which they are attached form a heterocyclic ring.
622. The salt of claim 621 wherein said salt is a tartaric acid salt.
623. The salt of claim 621 wherein said tartaric acid is L-(+)-tartaric acid.
624. The salt of claim 621 wherein said salt is a tartaric acid salt of a compound of Formula Va or a compound of Formula Vb.
625. The salt of claim 621 wherein:
. R2 is d-Cg allcyl, -CH2- -(Crd allcyl), C(O)O-(C C8 allcyl), -C(O)NH-(C C8 allcyl), OH, or
CH2OH; R3 and R6 are each H; R4 and R5 are each, independently, H, halo, Cι-C8 haloalkyl, hydroxy, OR9, alkoxyalkyl, NHR10, NR10Rπ, aryl, or heteroaryl, wherein said aryl can be substituted with up to two substituents selected from Crd alkyl, halo, C C8 haloallcyl, and alkoxy, and said heteroaryl can be optionally substituted with up to two substituents selected from halogen and d-d alkyl; or R4 and R5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; R7a is H; R7b is H or C,-d alkyl; R8a and R8b are each H; and R10 and R11 are each, independently, Cι-C8 alkyl, d-C8 alkenyl, Cι-C8 haloallcyl, aryl, heteroaryl, arallcyl, heteroarylallcyl, or allyl; provided that: (A) ifR2 is methyl and R4 is H, then R5 is not thiazole, substituted thiazole or a thiazole derivative; (B) if R7a is H and R7b is other than H, then neither R4 nor R5 can be H; (C) if R1 and R2 are methyl, and R5 is H then R4 is not NHR10 or NR^R1 '; and (D) ifR1 and R2 are methyl and R5 is H, then R4 is not imidazolyl, substituted imidazolyl, or an imidazole derivative.
626. The salt of claim 621 wherein: R2 is d-d alkyl, -CH2-0-(CrC4 alkyl), CrC4 haloalkyl, or CH2OH; R3 , R4, R5 , and R6 are each, independently, H, halo, C C4 alkyl, Crd haloallcyl, hydroxy, NH2, CN, or N02; and R7a s R7bj R8a ^ and R8b &χQ gach R. provided that: (TT) when R2 is CrC4 alkyl, -CH2-0-(CrC4 alkyl), or CH2OH, then R3 and R6 are not both H; and (I) when R2 is CH3, then R3, R4, and R6 are each H and R5 is not H or isopropyl.
627. The salt of claim 621 wherein R8a and R8b are each H.
628 The salt of claim 621 wherein R3 and R6 are each H.
629. The salt of claim 621 wherein R3, R5, and R6 are each H,
630. The salt of claim 621 wherein R4 is halo.
631. The salt of claim 621 wherein R4 is Cl.
632. The salt of claim 621 wherein R2 is CrC4 alkyl.
633. The salt of claim 621 wherein R2 is methyl.
634. The salt of claim 621 wherein R1 is H.
635. The salt of claim 621 wherein R1 is H or CrC4 alkyl, R2 is d-d allcyl, R3 is H, R4 is halo, R5 is H, R6 is H, R7a is H, R7b is H, R8a is H, and R8b is H.
636. The salt of claim 621 wherein R1 is H, R2 is Me, R3 is H, R4 is Cl, R5 is H, R6 is H, R7a is H, R7b is
H, Roa is H, and R 88bD : is H.
637. A composition comprising at least one chiral resolving acid salt of claim 621.
638. The composition of claim 637 wherein said composition comprises said tartaric acid salt form of a compound of Formula Va and said tartaric acid salt form of a compound of Formula Vb, wherein said composition is enriched in one of either of said tartaric acid salt form of a compound of Formula Va or said tartaric acid salt form of a compound of Formula Vb.
639. A hydrochloric acid salt of a compound of Formula Va or Vb:
Va Vb wherein: R1 is H or d-d alkyl; R2 is d-d alkyl, -CH2-0-(Cι-C8 alkyl), C(0)0-(C,-C8 alkyl), -C(0)NH-(C,-d alkyl), OH, Cr C4 haloallcyl, or CH2OH;
R3 , R4, R5 , and R6 are each, independently, H, halo, d-C8 alkyl, C2-C8 alkenyl, C2-C8 allcynyl, C3-C7 cycloallcyl, CrC8 haloalkyl, hydroxy, OR9, alkoxyalkyl, C(0)-alkyl, C(0)O-allcyl, C(0)NH-alkyl, hydroxyallcyl, NR10Rn, CN, N02, heterocycloallcyl, aryl, or heteroaryl, wherein said aryl and heteroaryl can be substituted with one or more substituents selected from Cι-C8 allcyl, halo, Cι-C8 haloallcyl, and alkoxy; or R4 and R5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; RSa and R8b are each, independently, H, halo, C C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloallcyl, C C8 haloalkyl, alkoxyallcyl, hydroxy, C(0)-alkyl, C(0)0-alkyl, C(0)NH-alkyl, or hydroxyallcyl, or R8a and R8b together with the carbon atom to which they are attached form a C3-C7 cycloalkyl group; R9 is H, Ci-Cg allcyl, d-d alkenyl, d-d alkynyl, C3-C7 cycloallcyl, Ci-Cg haloalkyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl; and R10 and Ru are each, independently, H, d- allcyl, Ci-Cg alkenyl, d-C8 alkynyl, C3-C7 cycloalkyl, d-d haloalkyl, arallcyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or R10 and R11 together with the N atom to which they are attached form a heterocyclic ring.
640. The salt of claim 639 wherein: R2 is C1-C4 alkyl, -CH2-0-(Cι-C4 allcyl), d-C4 haloallcyl, or CH2OH; R3 , R4, R5 , and R6 are each, independently, H, halo, C1-C4 alkyl, Cι-C haloallcyl, hydroxy, NH2, CN, or N02; and R7a , R7b, R8a , and R8b are each H; provided that: (H) when R2 is CrC4 alkyl, -CH2-0-(C C4 alkyl), or CH2OH, then R3 and R6 are not both H; and (I) when R2 is CH3, then R3, R4, and R6 are each H and R5 is not H or isopropyl.
641. The salt of claim 639 wherein R8a and R8b are each H.
642 The salt of claim 639 wherein R3 and R6 are each H.
643. The salt of claim 639 wherein R3, R5, and R6 are each H.
644. The salt of claim 639 wherein R4 is halo.
645. The salt of claim 639 wherein R4 is Cl.
646. The salt of claim 639 wherein R2 is CrC4 alkyl.
647. The salt of claim 639 wherein R2 is methyl.
648. The salt of claim 639 wherein R1 is H.
649. The salt of claim 639 wherein R1 is H or CrC4 alkyl, R2 is C C4 alkyl, R3 is H, R4 is halo, R5 is H, R6 is H, R7a is H, R7b is H, R8a is H, and R8b is H.
650. The salt of claim 639 wherein R1 is H, R2 is Me, R3 is H, R4 is Cl, R5 is H, R6 is H, R7a is H, R7b is H, R8a is H, and R8b is H.
651. A composition comprising at least one hydrochloric acid salt of claim 639.